BioMed Research International

BioMed Research International / 2018 / Article

Review Article | Open Access

Volume 2018 |Article ID 3819714 | 32 pages | https://doi.org/10.1155/2018/3819714

Natural Antispasmodics: Source, Stereochemical Configuration, and Biological Activity

Academic Editor: Juergen Buenger
Received24 Jul 2018
Accepted28 Aug 2018
Published08 Oct 2018

Abstract

Natural products with antispasmodic activity have been used in traditional medicine to alleviate different illnesses since the remote past. We searched the literature and compiled the antispasmodic activity of 248 natural compounds isolated from terrestrial plants. In this review, we summarized all the natural products reported with antispasmodic activity until the end of 2017. We also provided chemical information about their extraction as well as the model used to test their activities. Results showed that members of the Lamiaceae and Asteraceae families had the highest number of isolated compounds with antispasmodic activity. Moreover, monoterpenoids, flavonoids, triterpenes, and alkaloids were the chemical groups with the highest number of antispasmodic compounds. Lastly, a structural comparison of natural versus synthetic compounds was discussed.

1. Introduction

Antispasmodic compounds are currently used to reduce anxiety, emotional and musculoskeletal tension, and irritability. Although most of the available antispasmodic compounds are synthetic or semisynthetic, traditional uses of this group of compounds are still popular.

We collected information about natural compounds with antispasmodic activity isolated from terrestrial plants. We searched the databases of Google Scholar, PubMed, and SciFinder and compiled the information about 248 compounds published until December 2017. This review focuses on the antispasmodic activity of isolated compounds and activities from extracts without further purification are not discussed.

2. The Neurons

Nerve cells or neurons are responsible for receiving, conducting, and transmitting signals. A neuron consists of a nucleated body, a long thin extension called an axon, and several dendrites or prolongations extended from the cell body. Axons conduct signals from the nucleated body towards distant targets, while dendrites provide an enlarged surface area to receive signals from the axons of other neurons.

Signal transmission through axons is driven by a change in the electrical potential across the plasma membrane of neurons. This plasma membrane contains voltage-gated cation channels, which are responsible for generation of action potentials. An action potential is triggered by a depolarization of the plasma membrane or a shift to a less negative value.

In nerve and skeletal muscle cells, a stimulus can cause sufficient depolarization to open voltage-gated Na+ channels allowing the entrance of Na+ into the cell. This influx of Na+ depolarizes the membrane further causing the opening of more Na+ channels. To avoid a permanent influx, Na+ channels are able to reclose rapidly even when the membrane is still depolarized. This function is based on the presence of voltage-gated K+ channels, which are responsible for K+ efflux equilibrating the membrane potential even before the total inactivation of Na+ channels. In some cases, the action potential in some muscles depends on voltage-gated Ca2+ channels.

2.1. Transmission of Signals

The transmission of signals occurs mainly between neurons or from neurons to skeletal muscles, which are the final acceptors of electrical signals, causing a muscular contraction.

2.1.1. Signal Transmission between Neurons

Neuronal signals are transmitted between neurons at specialized sites of contact known as synapses. Neurons are separated by a synaptic cleft where a release of a neurotransmitter occurs. This neurotransmitter is stored in vesicles and is released by exocytosis. Upon triggering, the neurotransmitter is released into the cleft provoking an electrical change in the postsynaptic cell by binding to the transmitter-gated ion channels. To avoid a continuous electrical change and to ensure both spatial and temporal precision of signal transmission, the neurotransmitter is rapidly removed from the cleft either by specific enzymes in the synaptic cleft or by reuptake mediated by neurotransmitter carrier proteins [1].

Neurotransmitters can also open cation channels causing an influx of Na+ and then called excitatory neurotransmitters (e.g., acetylcholine, glutamate, and serotonin) or produce an opening of Cl- channels and then inhibiting the signal transmission by maintaining the postsynaptic membrane polarization [e.g., γ-aminobutyric acid (GABA) and glycine].

2.1.2. Neuromuscular Signal Transmission

The transmission of electrical signals to muscles involves five sequential and orchestrated steps: (i) nerve electric signal reaches the nerve terminal, (ii) it depolarizes the plasma membrane of the terminal, (iii) voltage-gated Ca2+ channels opens causing an increase in Ca2+ concentration in the neuron cytosol, and (iv) release of acetylcholine into the synaptic cleft is triggered. Acetylcholine binds to acetylcholine receptors in the muscle plasma membrane opening Na+ channels and provoking a membrane depolarization. This depolarization enhances the opening of more Na+ channels causing a self-propagating depolarization. The generalized depolarization of the muscle plasma membrane activates Ca2+ channels in specialized regions on the membrane causing Ca2+ release from the sarcoplasmic reticulum (Ca2+ storage) into the cytosol.

As a consequence of an increase in the Ca2+ concentration, myofibrils in the muscle cell contract. The increase of Ca2+ in the cytosol is transient because Ca2+ is rapidly pumped back into the sarcoplasmic reticulum causing a relaxation of the myofibrils. This process is very fast and Ca2+ concentration at resting levels is restored within 30 milliseconds [2].

3. Receptors

The autonomic nerve system controls and monitors the internal environment of the body. The input of its activity is provided by neurons that are associated with specific sensory receptors located in the blood vessels, muscles, and visceral organs (Table 1). According to the neurotransmitter secreted, these neurons are classified as adrenergic or cholinergic. The adrenergic neurons secrete the neurotransmitter noradrenalin termed also norepinephrine. Adrenergic receptors include the types α and β, which are further categorized as α1, α2, β1, β2, and β3. On the other hand, cholinergic neurons secrete acetylcholine, which induces a postsynaptic event. There are two types of cholinergic receptors, the nicotinic receptor (abundant at the neuromuscular junction) and the muscarinic receptor (abundant on smooth and cardiac muscles and glands).


ReceptorTargeted by

AdrenergicEpinephrine (adrenaline)
Norepinephrine (noradrenaline)
DopaminergicDopamine
CholinergicAcetylcholine
GABAergicGABA
GlutaminergicGlutamate
HistaminergicHistamine
SerotonergicSerotonin
GlycinergicGlycine
OpioidDynorphin
Enkephalin
Endorphin
Endomorphin
Nociceptin

There are several agonists (neurotransmitters, hormones, and others) able to bind to specific receptors and activate the contraction of smooth muscle. Upon binding the agonist to the receptor, the mechanism of contraction is based on an increase of phospholipase C. This enzyme hydrolyzes phosphatidylinositol 4,5-bisphosphate located on the membrane, producing two powerful secondary messengers termed diacylglycerol (DG) and inositol 1,4,5 triphosphate (IP3). IP3 binds to specific receptors in the sarcoplasmic reticulum, causing release of Ca2+ within the muscle. DG together with Ca2+ activates the protein kinase C (PKC), which phosphorylates specific proteins. In most smooth muscles, the contraction process commences when PKC phosphorylates Ca2+ channels or other proteins that regulate the cyclic process. For instance, Ca2+ binds to calmodulin (a multifunctional intermediate calcium-binding messenger protein), triggering the activation of the myosin light chain (MLC) kinase, which phosphorylates the light chain of myosin and together with actin carries out the process of initiating the shortening of the smooth muscle cell [147]. However, the elevation of the intracellular concentration of Ca2+ is transient, and the contractile response is maintained by a mechanism sensitized by Ca2+ modulated by the inhibition of myosin phosphatase activity by Rho kinase. This mechanism sensitized to Ca2+ is initiated at the same time that phospholipase C is activated and involves the activation of the small RhoA protein bound to guanosine triphosphate (GTP). Above activation, RhoA increases the activity of Rho kinase, leading to the inhibition of myosin phosphatase. This promotes the contractile state, since the myosin light chain cannot be dephosphorylated [147].

Relaxation of smooth muscle occurs as a result of either removing the contractile stimuli or by the direct action of a substance that stimulates the inhibition of the contractile mechanism. In any circumstance, the relaxation process requires a decrease in the intracellular Ca2+ concentration and an increase in the activity of the MLC phosphatase. The sarcoplasmic reticulum and plasma membrane remove Ca2+ from the cytosol. Na+/Ca2+ channels are located on the plasma membrane and help to reduce the intracellular concentration of Ca2+. During relaxation, other contributors that restrict the Ca2+ entry into the cell are the voltage-operated channels and Ca2+ receptors in the plasma membrane, which remain closed [147].

4. Spasmodic Compounds

The historical antecedents date from the year 1504 when South American natives inhabiting the basins of the high Amazon and the Orinoco prepared a mixture of alkaloids termed curare. This substance was placed in the tips of arrows in order to hunt (prey paralyzing) and fight in wars. Curare produces muscle weakness, paralysis, respiratory failure, and death [148]. In 1800, Alexander von Humboldt, identified that curare was made from the extracts of the species Chondrodendron tomentosum and Strychnos toxifera.

In 1935, the French physiologist Claude Bernard managed to isolate the alkaloid d-tubocurarine from the curare [149]; and one year later, it was elucidated that this compound had the ability to inhibit acetylcholine, blocking the transmission of nerve impulses to the muscles [150]. Lastly, new benzylisoquinoline alkaloids were isolated from curare by Galeffi et al. in 1977 [151, 152].

In 1822, the pharmacist Rudolph Brandes obtained an impure alkaloid from Atropa belladonna (Solanaceae), which after purification was named atropine. Interestingly, atropine was not produced as a natural compound from the plant and it was a derivative generated from the alkaloid hyoscyamine during the process of purification [153]. It is important to note that atropine has been naturally found in small quantities in other members of the Solanaceae family such as Datura stramonium, Duboisia myoporoides, and Scopolia japonica [154156].

The use of the plant Papaver somniferum (opium poppy) (Papaveraceae) dates back to about 4000 BC. At present the plant is only used to extract a base material for the manufacture of other alkaloids, such as noscapine and codeine, both discovered by the French pharmacist Pierre-Jean Robiquet in 1831 and 1832, respectively [157]. In 1848, papaverine was another substance extracted from the same plant by the German chemist Georg Merck [158], which is rarely used today because of the high doses needed (approximately 6 to 12 mg). However, it is still used as a control in experimental models with the purpose of studying antispasmodic activity of plant extracts.

In the century, extracts and powders derived from A. belladonna were widely used as antispasmodics, but from the 1950s these preparations were displaced by synthetic and semisynthetic anticholinergic compounds in order to obtain a better response [159], such as the case of methocarbamol and guaifenesin. On the other hand, a series of compounds such as dantrolene, glutethimide, methaqualone, chlormezanone, metiprilone, and ethchlorvynol were introduced to replace the meprobamate, which had to be withdrawn from the market in 1960 due to problems resulting from use such as abstinence, addictions, and overdoses.

In 1962, the Swiss chemist Heinrich Keberle synthesized baclofen, which can be obtained by reacting glutarimide with an alkaline solution [160]. Glutarimide can also be found in plants such as Croton cuneatus and C. membranaceus (Euphorbiaceae) [161, 162].

The arrival of the quaternary compounds of nitrogen reinforce their peripheral anticholinergic activity offering also the advantages of being poorly absorbed in the gastrointestinal tract, producing a more powerful and longer lasting sedative effect unlike atropine [1]. For example, ipratropium bromide was developed by the German company Boehringer Ingelheim in 1976 and used to treat asthma. This compound was obtained by reacting atropine with isopropyl bromide [163]. Another quaternary compound was the n-butylhyoscine bromide, which is possible to obtain by the organic synthesis of scopolamine and the cimetropium bromide found in the A. belladonna [164]. Although at present the preparations of plant mixtures are no longer used for therapeutic purposes, these compounds formed a part of and served as the basis for modern pharmacology for their applicability as antispasmodics and anesthetics.

Spasms are involuntary contractions of the muscles, which are normally accompanied by pain and interfere with the free and effective muscular voluntary activity. Muscle spasm can originate from multiple medical conditions and is often associated with spinal injury, multiple sclerosis, and stroke.

Spasticity and rigidity are caused by a disinhibition of spinal motor mechanisms. There are several scenarios where a muscle can produce a spasm: (i) unstable depolarization of motor axons; (ii) muscular contractions persist even if the innervation of muscle is normal and despite attempts of relaxation (myotonia); (iii) after one or a series of contractions, the muscle can decontract slowly, as occurring in hypothyroidism; and (iv) muscles lack the energy to relax.

4.1. Distribution of Spasmodic Compound in Nature

Spasmodic compounds are widely distributed in nature (Table 2). Frequently, these compounds are found in animals that paralyze their preys or used for defense. Some examples include the venom of the black widow and tarantula spiders [11, 165] and the venom of snakes [166]. Plants also produce spasmodic metabolites, such as strychnine, an alkaloid obtained from the tree Strychnos nux-vomica (Loganiaceae). Furthermore, microorganisms synthesize spasmodic compounds such as the neurotoxins tetanospasmin and botulinum toxin from the Gram-positive bacteria Clostridium tetani and C. botulinum, respectively. These toxins produce a toxic disorder, which is characterized by persistent spasms of skeletal muscles on spinal neurons similar to strychnine.


CompoundOrganismSymptomsMechanismReference

Bacterial
Botulinum toxinClostridium botulinumMuscular relaxationSecretion of acetylcholine into synapses is blocked[3]
TetanospasminClostridium tetaniMuscular spasmInhibits the binding of GABA and glycine[4]

Marine
Nematocyst venom extractSea anemonesNausea, vomiting, muscle cramp, severe pain, paralysisDelay in the voltage-dependent Na+ channels inactivation[5]
Nematocyst venom extractChironex fleckeri (Cnidaria)Contraction of arterial smooth muscleIncrease of cytosolic Ca2+ concentration[6]
CiguatoxinGambierdiscus toxicus (Dinoflagellate)Nausea, vomiting, abdominal pain, intestinal spasmInteract with voltage-gated increasing the Na+ permeability and Ca2+ homeostasis[7]
ChordataPlotosus lineatus (Catfish)Violent pain, shock, spasmIncrease of the vascular permeability in peritoneum[8]

Terrestrial
ErgotamineClaviceps purpurea (fungus)Seizure, spasms psychosis, nausea, vomitingAgonist of several neurotransmitter receptors[9]
α-LatrotoxinLatrodectus tredecimguttatus (black widow spider)Facial flushing, hypertension, muscle spasm, tachycardiaCauses Ca2+-dependent and -independent release of neurotransmitters[10]
Vanillo-toxin, hanatoxin, huwentoxinTarantula speciesSevere pain, cramps, erythema, swelling, tachycardiaUnrevealed[1114]
β-NeurotoxinMesobuthus martensii (scorpion)Increases muscular contraction, spasm, convulsionModulates Ca2+ channels[15]
CrotoxinCrotalus durissus terrificus (rattlesnake)Severe pain, drooping eyelids, low blood pressure, muscle weaknessBlocks the cholinergic post-synaptic response[16]

4.2. Mechanisms of Antispasmodic Activity of Natural Products

Antispasmodic compounds exert their activity in different ways, such as antispasmodic activity through inhibition of the response to the neurotransmitters 5-hydroxytryptamine (5-HT) or serotonin and acetylcholine. However, other authors attribute the antispasmodic effect to (i) capsaicin-sensitive neurons, (ii) the participation of vanilloid receptors [167], (iii) the activation of K+ ATP channels, (iv) the blockade of Na+ channels and muscarinic receptors, (v) the reduction of extracellular Ca2+, or (vi) the blockade of Ca2+ channels [22, 168, 169]. The above is merely a reflection of the ambiguity of the studies showing the mechanisms of action of the antispasmodic compounds [36]. For example, the hydroalcoholic extract of Marrubium vulgare showed antispasmodic effect, having the ability to inhibit the neurotransmitters acetylcholine, bradykinin, prostaglandin E2, histamine, and oxytocin [170], whereas a dual effect of antidiarrheal and laxative activities was reported in Fumaria parviflora [171].

5. Methods Used to Evaluate Antispasmodic Compounds

5.1. Gastrointestinal Model

The small intestine is characterized by its large surface area as a result of its circular folds, villi, and microvilli. It is the longest part of the GI system (approximately 5 meters) and comprises about 5% of its initial length, which corresponds to the duodenum (characterized by the absence of the mesentery) and then the jejunum (around 40% of the intestinal length), ending with the ileum. It is the organ of absorption of nutrients and digestion in organisms. These functions are carried out mainly in the duodenum and jejunum.

The main types of bowel movement are the segmentation and peristaltism. The segmentation is most frequent in the small intestine and consists of contractions of the circular muscle layer in very close areas. Contractions last for 11-12 and 8-9 contractions per min in the duodenum and ileum, respectively. When this segmentation is rhythmic, the contractions are alternated with relaxation. This type of movement results in a mixed effect of the chyme (acidic fluid that passes from the stomach to the small intestine) with the digestive secretions, allowing an optimal contact with the intestinal mucosa. In the case of peristalsis, contractions of successive sections of the circular smooth muscle cause the movement of the intestinal contents in anterograde form. The short peristaltic movement also takes place in the small intestine, but less frequently than the segmentation movements. Peristaltic waves rarely cross more than 10 cm of intestine and, due to the low frequency of propulsion of the chyme, it is in this zone where digestion and absorption are preferably carried out. Peristalsis is regulated mainly by the nervous action of the myenteric plexus (major nerve supply to the gastrointestinal tract that controls GI tract motility) in the intestinal wall.

The diversity of experimental models used for the testing of antispasmodic compounds is large. These models mainly use isolated organs or live animals. Once the organ is extracted from the animal, the intestinal motility is assessed with the administration of a substance. The use of extracted organs can be sustained for hours when placed in a physiological solution, such as Ringer, Jalon, Tyrode, and Krebs [172].

The most used organs to perform the studies are guinea pig ileum, duodenum, heart, trachea, and jejunum. The same organs can be also extracted from rabbit, mouse, rat, and hamster (Table 3). The preparation of ileum is preferred because it evaluates the spasmolytic activity. However, although the jejunum contracts spontaneously, it allows evaluating the spasmolytic activity directly and without the use of an agonist [173].


Compound nameSpecies (Family)Preparation (Solvent)Model testedSourceReference

Monoterpenoids
1 Myrcene, β-myrcenePlectranthus barbatus (Lamiaceae)Leaf (MeOH)ACh, BaCl2, KCl in guinea pig ileumEO[17]
2 Citral B, β-citral, NeralAloysia triphylla (Verbenaceae)Leaf (Hexane)Carbachol, KCl, O, PGF (2α) in rat uterusIC[18]
Cymbopogon citratus (Poaceae)Leaf (MeOH 70%)ACh, KCl in rabbit ileumIC[19]
Melissa officinalis (Lamiaceae)Aerial part (EtOH 70%)ACh, KCl in rat ileumEO[20]
3 Geranyl formateAnthemis mauritiana (Compositae)Flower (Distillation)Ca2+, carbachol, KCl in rabbit and rat jejunumEO[21]
4 Geranyl acetateNepeta cataria (Lamiaceae)Leaf (Aqueous)Carbachol, KCl in guinea pig trachea and rabbit jejunumEO[22]
5 GeraniolRosa damascene (Rosaceae)Flower (hydrodistillation)ACh, KCl, electrical field stimulation in rat ileumIC[23]
6 CitronellolRosa damascene (Rosaceae)Flower (hydrodistillation)ACh, KCl, electrical field stimulation in rat ileumIC[23]
7 (±)--PhellandreneZingiber officinale (Zingiberaceae)Rhizome (MeOH)Serotonin in rat ileumEO[24]
8 (±)--PhellandreneCroton sonderianus (Euphorbiaceae)Leaf (Distillation)ACh, KCl in rat tracheal smooth muscleEO[25]
9 TerpinoleneZingiber officinale (Zingiberaceae)Rhizome (MeOH)Serotonin in rat ileumEO[24]
10 D-(+)-LimoneneZingiber roseum (Zingiberaceae)Fresh seeds (Hydrodistilled with diethyl ether)Carbachol, KCl in rat duodenal smooth muscleEO[26]
Mentha x villosa (Lamiaceae)Leaf infusion (MeOH)KCl in guinea pig ileumIC[27]
Dracocephalum kotschyi (Lamiaceae)Aerial part (Hydrodistillation)ACh, electrical field stimulation, KCl in rat ileumEO[28]
11  -TerpineneAcalypha phleoides (Euphorbiaceae)Aerial part infusion MeOH-CHCl3 (1:1)ACh, BaCl2, H, S in guinea pig ileum and rabbit jejunumIC[29]
12 ThymoquinoneNigella sativa (Ranunculaceae)Seed infusion (Aqueous)BaCl2, carbachol, leukotriene in rat tracheaIC[30]
13 (R)-(+)-PulegoneCalamintha glandulosa (Lamiaceae)Aerial parts infusion (Diethyl ether)KCl in rat ileumIC[31]
Mentha x villosa (Lamiaceae)Leaf infusion (MeOH)KCl in guinea pig ileumIC[27]
14 (-)-MentholMentha piperita (Lamiaceae)Leaf and flower infusion (EtOH)S in rat ileumIC[32]
15 dl--TerpineolCasimiroa pringlei (Rutaceae)Aerial part infusion (Ethylic ether)KCl in rat uterine smooth muscleIC[33]
Zingiber roseum (Zingiberaceae)Fresh seeds (Hydrodistilled with diethyl ether)Carbachol, KCl in rat duodenal smooth muscleEO[26]
Dracocephalum kotschyi (Lamiaceae)Aerial part (Hydrodistillation)ACh, electrical field stimulation, KCl in rat ileumEO[28]
16 (-)-PiperitoneCasimiroa pringlei (Rutaceae)Aerial part infusion (Ethylic ether)KCl in rat uterine smooth muscleIC[33]
17 (+)-RotundifoloneMentha x villosa (Lamiaceae)Leaf infusion (MeOH)KCl in guinea pig ileumIC[27]
18 ()-(-)-CarvoneMentha x villosa (Lamiaceae)Leaf infusion (MeOH)KCl in guinea pig ileumIC[27]
19 (R,R,R)-Carvone-1,2-oxide)Mentha x villosa (Lamiaceae)Leaf infusion (MeOH)KCl in guinea pig ileumIC[27]
20 (S)-(+)-CarvoneMentha x villosa (Lamiaceae)Leaf infusion (MeOH)KCl in guinea pig ileumIC[27]
21 1,8-CineoleOcimum gratissimum (Lamiaceae)Leaf infusion (MeOH)ACh, KCl in guinea pig ileumIC[34]
Nepeta cataria (Lamiaceae)Leaf infusion (Aqueous)Carbachol, KCl in guinea pig trachea and rabbit jejunumEO[22]
Casimiroa pringlei (Rutaceae)Aerial part infusion (Ethylic ether)KCl in rat uterine smooth muscleIC[33]
22  p-CymeneLippia graveolens (Verbenaceae)Leaf infusion (Distillation)Carbachol, H in guinea pig ileumIC[35]
Zingiber roseum (Zingiberaceae)Fresh seeds (Hydrodistilled with diethyl ether)Carbachol, KCl in rat duodenal smooth muscleEO[26]
Poliomintha longiflora (Lamiaceae)Leaves stem infusion (Distillation)Carbachol, H in guinea pig ileumIC[35]
23 CarvacrolOriganum acutidens (Lamiaceae)Leaf, stem and flower infusion (MeOH)Spontaneous contraction in rat ileumEO[36]
Thymus vulgaris (Lamiaceae)Whole plants (Ethanol)ACh, BaCl2, KCl in rat trachea and ileumIC[37]
24 ThymolAcalypha phleoides (Euphorbiaceae)Aerial part infusion [MeOH-CHCl3 (1:1)]ACh, BaCl2, H, KCl, S in guinea pig ileum and rabbit jejunumIC[29]
Thymus vulgaris (Lamiaceae)Whole plants (Ethanol)ACh, BaCl2, KCl in rat trachea and ileumIC[37]
25 Thujane or SabinaneAnthemis mauritiana (Asteraceae)Flower infusion (Aqueous)Carbachol, KCl in rabbit jejunal smooth muscleEO[21]
26 (±)-CamphorAcalypha phleoides (Euphorbiaceae)Aerial part infusion [MeOH-CHCl3 (1:1)]ACh, BaCl2, H, KCl, S in guinea pig ileum and rabbit jejunumIC[29]
Lippia dulcis (Verbenaceae)Leaf infusion (Steam distillation)Carbachol, H in porcine bronchiEO[38]
27 (+)--PineneAnthemis mauritiana (Asteraceae)Flower infusion (Aqueous)Carbachol, KCl in rabbit jejunal smooth muscleEO[21]
Nepeta cataria (Lamiaceae)Leaf infusion (Aqueous)Carbachol, KCl in guinea pig trachea and rabbit jejunumEO[22]
Plectranthus barbatus (Lamiaceae)Leaf infusion (MeOH)ACh, BaCl2, H, KCl in guinea pig ileumEO[17]
28 (-)--PineneDissotis rotundifolia (Melastomataceae)Leaf infusion (EtOH)Carbachol in mouse intestinal motilityE[39]
Eucalyptus tereticornis (Myrtaceae)CommercialACh, KCl in rat tracheaEO[40]
Zingiber roseum (Zingiberaceae)Fresh seeds (Hydrodistilled with diethyl ether)Carbachol, KCl in rat duodenal smooth muscleEO[26]
29 (+)--PineneFerula gummosa (Apiaceae)Resin infusion (Hydroalcoholic, ether, MeOH)ACh, KCl in rat ileumIC[41]
Zingiber officinale (Zingiberaceae)Rhizome infusion (MeOH)S in rat ileumEO[24]
Zingiber roseum (Zingiberaceae)Fresh seeds (Hydrodistilled with diethyl ether)Carbachol, KCl in rat duodenal smooth muscleEO[26]
30 CantleyineStrychnos trinervis (Loganiaceae)Root bark (EtOAc)Carbachol, H, KCl in guinea pig tracheaIC[42]
31 PenstemonosideParentucellia latifolia (Scrophulariaceae)Whole plant infusion (Butanol)ACh, CaCl2, KCl in rat uterusIC[43]
32 Aucubine or aucubosideParentucellia latifolia (Scrophulariaceae)Whole plant infusion (Butanol)ACh, CaCl2, KCl in rat uterusIC[43]
33 2′-O-AcetyldihydropenstemideViburnum prunifolium (Caprifoliaceae)Root and stem bark infusion (MeOH)Carbachol in rabbit jejunum and guinea pig tracheaE[44]
34 2′-O-trans-p-Coumaroyl-dihydropenstemideViburnum prunifolium (Caprifoliaceae)Root and stem bark infusion (MeOH)Carbachol in rabbit jejunum and guinea pig tracheaE[44]
35 2′-O-AcetylpatrinosideViburnum prunifolium (Caprifoliaceae)Root and stem bark infusion (MeOH)Carbachol in rabbit jejunum and guinea pig tracheaE[44]
36 PatrinosideViburnum prunifolium (Caprifoliaceae)Root and stem bark infusion (MeOH)Carbachol in rabbit jejunum and guinea pig tracheaE[44]
37 Valtriate or ValepotriateValeriana procera (Valerianeaceae)Root infusion (EtOH)BaCl2, carbachol, KCl in guinea pig ileum and stomachIC[45]
38 Isovaltrate or IsovaltratumValeriana procera (Valerianeaceae)Root infusion (EtOH)BaCl2, carbachol, KCl in guinea pig ileum and stomachIC[45]
39 EpoxygaertnerosideMorinda morindoides (Rubiaceae)Leaf infusion (Aqueous)ACh, KCl in guinea pig ileumIC[46]
40 GaertnerosideMorinda morindoides (Rubiaceae)Leaf infusion (Aqueous)ACh, KCl in guinea pig ileumIC[46]
41 Catalpinoside or CatapolParentucellia latifolia (Scrophulariaceae)Whole plant infusion (Butanol)ACh, CaCl2, KCl in rat uterusIC[43]

Sesquiterpenes
43 (±)-HernandulcinLippia dulcis (Verbenaceae)Leaf infusion (Steam distillation)Carbachol, H in porcine bronchiEO[38]
43 Humulene or α-CaryophylleneNepeta cataria (Lamiaceae)Leaf infusion (Aqueous)Carbachol, KCl, in guinea pig trachea and rabbit jejunumEO[22]
44β-Caryophyllene epoxideConyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
Croton sonderianus (Euphorbiaceae)Leaf infusion (Steam distillation)ACh, KCl in rat tracheal smooth muscleEO[25]
45β-CaryophylleneCroton sonderianus (Euphorbiaceae)Leaf infusion (Steam distillation)ACh, KCl in rat tracheal smooth muscleEO[25]
Conyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
Plectranthus barbatus (Lamiaceae)Leaf infusion (MeOH)ACh, BaCl2, H, KCl in guinea pig ileumEO[17]
Pterodon polygalaeflorus (Fabaceae)Seed (Steam distillation)ACh, KCl in rat ileum smooth muscleIC[48]
46 Bicyclogermacrene or LepidozeneCroton sonderianus (Euphorbiaceae)Leaf infusion (Steam distillation)ACh, KCl in rat tracheal smooth muscleEO[25]
47 (+)-CapsidiolNicotiana silvestri (Solanaceae)Leaf infusion (EtOAc)ACh, BaCl2, bradykinin, carbachol in guinea pig ileum and tracheaIC[49]
48 S-PetasinPetasites formosanus (Compositae)Aerial parts (EtOH)CaCl2, carbachol, H, KCl in guinea pig tracheaIC[50]
49 (+)-IsopetasinPetasites formosanus (Compositae)Aerial parts (EtOH)CaCl2, carbachol, H, KCl in guinea pig tracheaIC[50]
50 Valeranone o JatamansoneValeriana procera (Valerianeaceae)Root infusion (EtOH)BaCl2, carbachol, KCl in guinea pig ileum and stomachIC[45]
51 ChamazuleneMatricaria recutita (Asteraceae)Plant infusion (Aqueous)Human plateletE[51]
52 SpathulenolCroton sonderianus (Euphorbiaceae)Leaf infusion (Steam distillation)ACh, KCl in rat tracheal smooth muscleEO[25]
Lepechinia caulescens (Lamiaceae)Leaf infusion (Hexane)KCl in rat uterusIC[52]
53 CynaropicrinCynara scolymus (Asteraceae)Leaf and flower infusion (MeOH 70%)ACh in guinea pig ileumIC[53]
54 CedrenolAnthemis mauritiana (Asteraceae)Flower infusion (Aqueous)Carbachol, KCl in rabbit jejunal smooth muscleEO[21]
55 (+)-Bakkenolide AHertia cheirifolia (Asteraceae)Aerial parts (MeOH)ACh, BaCl2 in rat duodenumIC[54]
56 HimachalolCedrus deodara (Pinaceae)Wood infusionACh, BaCl2, H, nicotine, S in guinea pig ileum and seminal vesicle, rabbit jejunum and rat uterusIC[55]
57 (E)-DamascenoneIpomoea pes-caprae (Convolvulaceae)Leaf infusion (Aqueous)H in guinea pig ileal smooth muscleIC[56]
58 (-)-Isogermacrene DArtemisia vulgaris (Compositae)Stem and leaf infusion (Aqueous)guinea pig ileum[57]
59 EzoalantoninArtemisia vulgaris (Compositae)Leaf (CHCl3)H, PMA, S in guinea pig ileum and tracheaIC[57]
60 CostunolideRadix aucklandiae (Asteraceae)Rhizome (MeOH)ACh, KCl, S in rat jejunumIC[58]
61 DehydrocostuslactoneRadix aucklandiae (Asteraceae)Rhizome (MeOH)ACh, KCl, S in rat jejunumIC[58]

Diterpenes
62 E-PhytolIpomoea pes-caprae (Convolvulaceae)Leaf infusion (Aqueous)H in guinea pig ileal smooth muscleIC[56]
63 3α-Angeloyloxy-2α-hydroxy-13,14Z-dehydrocativic acidBrickellia paniculata (Compositae)Leaf infusion (MeOH)KCl in rat myometrial tissueIC[59]
64 15-Epicyllenin AMarrubium globosum ssp. libanoticum (Lamiaceae)Aerial part infusion (MeOH)ACh in mouse ileumIC[60]
65 Cyllenin AMarrubium globosum ssp. libanoticum (Lamiaceae)Aerial part infusion (MeOH)ACh in mouse ileumIC[60]
66 MarrulibacetalMarrubium globosum ssp. libanoticum (Lamiaceae)Aerial part infusion (MeOH)ACh in mouse ileumIC[60]
67 (13R)-9α,13α-epoxylabda-6β(19),16(15)-diol dilactoneMarrubium globosum ssp. libanoticum (Lamiaceae)Aerial part infusion (MeOH)ACh in mouse ileumIC[60]
68 MarrubinMarrubium vulgare (Lamiaceae)Aerial parts (Aqueous)KCl in rat aortaIC[61]
69 Marrubenol or MarrubiolMarrubium vulgare (Lamiaceae)Aerial parts (Aqueous)KCl in rat aortaIC[61]
70 Marrulanic acidMarrubium globosum ssp. libanoticum (Lamiaceae)Aerial part infusion (MeOH)ACh in mouse ileumIC[60]
71 MarrulactoneMarrubium globosum ssp. libanoticum (Lamiaceae)Aerial part infusion (MeOH)ACh in mouse ileumIC[60]
72 (+)-Dehydroabietic acidLepechinia caulescens (Lamiaceae)Leaf infusion (Hexane)KCl in rat uterusIC[52]
73 9β-Hydroxydehydroabietyl alcoholLepechinia caulescens (Lamiaceae)Leaf infusion (Hexane)KCl in rat uterusIC[52]
74 9α,13α-Epidioxyabiet-8(14)-en-18-oic acid methyl esterLepechinia caulescens (Lamiaceae)Leaf infusion (Hexane)KCl in rat uterusIC[52]
75 4-epi-Hyalic acidCroton argyrophylloides (Euphorbiaceae)Bark infusion (MeOH)ACh, KCl in rat tracheal smooth muscleIC[62]
76 Pimaradienoic acid or Continentalic acidViguiera arenaria (Asteraceae)Root infusion (CH2Cl2)ACh, KCl in rat carotid arteryIC[63]
77 8(14),15-Sandaracopimaradiene-7α,18-diolTetradenia riparia (Lamiaceae)Leaf infusion (CHCl3)BaCl2, H, methacholine in guinea pig ileumIC[64]
78 3,4-Secoisopimara-4(18),7,15-triene-3-oic acidSalvia cinnabarina (Lamiaceae)Aerial parts (EtOH)ACh, BaCl2, H in guinea pig ileumIC[65]
79 ent-Kaurenoic acidViguiera arenaria (Asteraceae)Root infusion (CH2Cl2)ACh, KCl in rat carotid arteryIC[63]
Viguiera hypargyrea (Asteraceae)Root infusion (Hexane)Spontaneous contraction in guinea pig ileumIC[66]
80 Beyerenic acid or Monogynoic acidViguiera hypargyrea (Asteraceae)Root infusion (Hexane)Spontaneous contraction in guinea pig ileumIC[66]
81 ent-7α-Acetoxytrachyloban-18-oic acidXylopia langsdorfiana (Annonaceae)Stem infusion (EtOH 95%)BaCl2, H, KCl in guinea pig ileumIC[67]
82 ent-7α -hydroxytrachyloban-18-oic acidXylopia langsdorfiana (Annonaceae)Stem infusion (EtOH 95%)BaCl2, H, KCl in guinea pig ileumIC[67]
83 Phorbol 12-acetate-13-tiglateCrotonis tiglium (Euphorbiaceae)Fruit (MeOH)Spontaneous contraction in rabbit jejunumE[68]
84 3,7,10,14,15-pentaacetyl-5-butanoyl-13,17-epoxy-8-myrsinenePycnocycla spinosa (Umbelliferae)Aerial parts (MeOH)KCl in rat illeumIC[69]

Triterpenoids
85 Agapanthagenin 3-O-β-D-glucopyranosideAllium elburzense (Alliaceae)Flower and bulb infusion (Hexane)H in guinea pig ileumIC[70]
86 AgapanthageninAllium elburzense (Alliaceae)Flower and bulb infusion (Hexane)H in guinea pig ileumIC[70]
87β-sitosterolEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[71]
88 β-sitosterol 3-O-β-D-glucopyranosideEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[71]
89 α-Spinasteryl β-D-glucosideConyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
90 Tropeoside B1 and B2Allium cepa(Alliaceae)Bulbs [CHCl3:MeOH (9:1)]ACh, H in guinea pig ileumIC[72]
91 Tropeoside A1 and A2Allium cepa(Alliaceae)Bulbs [CHCl3:MeOH (9:1)]ACh, H in guinea pig ileumIC[72]
92 Elburzensoside A1 and A2Allium elburzense (Alliaceae)Flower and bulb infusion (Hexane)H in guinea pig ileumIC[70]
93 Elburzensoside C1 and C2Allium elburzense (Alliaceae)Flower and bulb infusion (Hexane)H in guinea pig ileumIC[70]
94 Galphimin AGalphimia glauca (Malpighiaceae)Leaf infusion (MeOH)Electrical-induced contraction in guinea pig ileumIC[73]
95 Galphimin BGalphimia glauca (Malpighiaceae)Leaf infusion (MeOH)Electrical-induced contraction in guinea pig ileumIC[73]
96 Galphimin CGalphimia glauca (Malpighiaceae)Leaf infusion (MeOH)Electrical-induced contraction in guinea pig ileumIC[73]
97 Galphimin EGalphimia glauca (Malpighiaceae)Leaf infusion (MeOH)Electrical-induced contraction in guinea pig ileumIC[73]
98 Galphimin FGalphimia glauca (Malpighiaceae)Leaf infusion (MeOH)Electrical-induced contraction in guinea pig ileumIC[73]
99 HandianolHerissanthia tiubae (Malvaceae)Leaf infusion (EtOH)Carbachol, H, KCl in guinea pig ileum and trachea, and rat aortaIC[74]
100 CycloartanolHerissanthia tiubae (Malvaceae)Leaf infusion (EtOH)Carbachol, H, KCl in guinea-pig ileum, trachea and rat aortaIC[74]
101 Taraxasteryl acetateBrickellia veronicifolia (Asteraceae)Aerial parts [CH2Cl2:MeOH (1:1)]Gastrointestinal motility test in mouseE[75]
102 Pomolic acid or Benthamic acid or Randialic acid ALicania pittieri (Rosaceae)Leaf infusion (EtOH)Carbachol, KCl in rat aortaIC[76]
103 Ursolic acidAgastache mexicana (Lamiaceae)Aerial part (MeOH)ACh, KCl in guinea pig ileumIC[77]
104 EhretiolideEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[78]
105 Ehretiolide acetateEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[78]
106 CamaldulinEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[71]
107 Zygophyloside NZygophyllum gaetulum (Zygophyllaceae)Root infusion (MeOH)Electrically-induced contractions of isolated guinea pig ileumE[79]
108 ErythrodiolConyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
109 3-β-tridecanoyloxy-28-hydroxyolean-12-eneConyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
110 3--Hydroxyolean-9(11),12-dien-28-oic acidEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[78]
111 4-epi-HederageninHedera helix (Araliaceae)Leaf infusion (EtOH)ACh in guinea pig ileumIC[80]
112 Hederacoside CHedera helix (Araliaceae)Leaf infusion (EtOH)ACh in guinea pig ileumIC[80]
113 Betulinic acidEucalyptus camaldulensis (Myrtaceae)Leaf infusion (EtOAc)KCl, spontaneous contraction in rabbit jejunumIC[78]
114 α-Amyrin acetateTylophora hirsuta (Asclepiadaceae)Aerial parts (MeOH)KCl in rabbit jejunumIC[81]

Phloroglucinol derivatives
115 HyperforinHypericum perforatum (Hypericaceae)Aerial parts (EtOH 70%)KCl in rabbit jejunumIC[82]
116 HypericinHypericum perforatum (Hypericaceae)Aerial parts (EtOH 70%)KCl in rabbit jejunumIC[82]

Coumarins
117 ScopoletinBrunfelsia hopeana (Solanaceae)Root infusion (EtOH)Phenylephrine, KCl, PGF2, serotonin in rat aortaIC[83]
118 TodannoneToddalia asiatica var. floribunda (Rutaceae)Aerial parts (EtOH 95%)ACh, BaCl2, H, nicotine in guinea pig ileumIC[84]
119 (2S,3R)-2-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-2,3-dihydro-7-hydroxy-2,3-dimethylfuro[3,2c] coumarinFerula heuffelii (Apiaceae)Underground part (CHCl3)ACh, KCl in rat ileumIC[85]
120 OstholePrangos ferulacea (Apiaceae)Root (Acetone)ACh, KCl, electric field stimulation in rat ileumIC[86]
121 AngelicinHeracleum thomsoni (Apiaceae)Aerial part infusion (EtOH)ACh, BaCl2, H, S in cat ureter, guinea pig bile duct and trachea, monkey gall bladder, rabbit jejunum, and rat uterusIC[87]
122 GlycycoumarinGlycyrrhizae radix (Leguminosae)Root infusion (Aqueous)A23187, BaCl2, carbachol, KCl in mouse jejunumIC[88]
Glycyrrhiza ularensis (Leguminosae)Root infusion (Aqueous)Carbachol in mouse jejunumE[89]

Chalcones
123 DavidigeninMascarenhasia arborescens (Apocynaceae)Leaf and stem infusion (MeOH)ACh, H in guinea pig and rat duodenumIC[90]
124 IsoliquiritigeninGlycyrrhiza glabra (Leguminosae)Root infusion (Aqueous)ACh, KCl, O, spontaneous contraction in rat uterusIC[91]
Glycyrrhiza ularensis (Leguminosae)Root infusion (Aqueous) (Aqueous)BaCl2, carbachol, KCl in mouse jejunum,ileum and rectumIC[92]
125 Licochalcone AGlycyrrhiza inflata (Leguminosae)Root infusion (Aqueous)A23187, BaCl2, carbachol, KCl in mouse jejunumIC[93]

Flavonoids
126 (-)-PinostrobinConyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
127 (-)-(S)-SakuranetinDodonaea viscosa (Sapindaceae)Leaf infusion [CHCl3:MeOH (1:1)]ACh, BaCl2, H in rat uterusIC[94]
128 (±)-SternbinArtemisia monosperma (Compositae)Aerial part (EtOH)ACh, O in rat ileum, pulmonary artery, urinary bladder, trachea, and uterusIC[95]
129 Ouratea catechinMaytenus rigida (Celastraceae)Stem bark (EtOH)BaCl2, carbachol, KCl, H in guinea pig ileumIC[96]
130 ApegeninAchillea millefolium (Asteraceae)Whole plant infusion (MeOH 40%)ACh, CaCl2, H, PE, S in rat ileumIC[97]
131 Buddleoflavonol or LinarigeninAgastache mexicana (Lamiaceae)Aerial part (MeOH)ACh, KCl in guinea pig ileumIC[77]
132 LuteolinAchillea millefolium (Asteraceae)Whole plant infusion (MeOH 40%)ACh, CaCl2, H, PE, S in rat ileumIC[97]
Artemisia copa (Compositae)Aerial parts (Aqueous)KCl, PE, S in rat aortaE[98]
Plantago lanceolata (Plantaginaceae)Aerial part (EtOH)ACh, BaCl2, H, KCl in guinea pig ileum and tracheaIC[99]
Thymus vulgaris (Lamiaceae)Leaf and flower (EtOH)ACh, BaCl2, carbachol, H in guinea pig ileum and trachea, and rat vas deferensIC[100]
133 Scutellarein 6-β-D-glucoside (isovitexin)Aloysia citridora (Verbenaceae)Leaf infusion (Aqueous)ACh, CaCl2, KCl in rat duodenumIC[101]
134 VitexinAloysia citridora (Verbenaceae)Leaf infusion (Aqueous)ACh, CaCl2, KCl in rat duodenumIC[101]
Aspalathus linearis (Fabaceae)Commercial (Aqueous)KCl in rabbit jejunumIC[102]
135 XanthomycrolBrickellia paniculata (Compositae)Leaf infusion (MeOH)KCl, O in rat uterusIC[59]
136 DemethoxycentaureidinPiptadenia stipulacea (Leguminosae)Aerial parts, (CHCl3)Carbachol, H, O, in guinea pig ileum and trachea, rat aorta and uterusIC[103]
137 Gnaphaliin BGnaphalium liebmannii (Asteraceae)Aerial parts (Hexane)ACh, carbachol in guinea pig tracheaIC[104]
138 Kaempferol or KaempherolHedera helix (Araliaceae)Aerial parts (EtOH 30%)ACh in guinea pig ileumIC[80]
139 Gnaphaliin AGnaphalium liebmannii (Asteraceae)Aerial parts (Hexane)ACh, carbachol in guinea pig tracheaIC[104]
140 QuercetinAchillea millefolium (Asteraceae)Whole plant infusion (MeOH 40%)ACh, CaCl2, H, PE, serotonin in rat ileumIC[97]
Psidium guajava (Myrtaceae)Leaf extract (MeOH)Peristalsis in guinea pig ileumIC[105]
Drosera madascariensis (Droseraceae)Leaf extract (EtOH 70%)Carbachol, H, PGF2 in guinea pig ileum and tracheaIC[106]
Drosera rotundifolia (Droseraceae)Aerial parts (EtOH 70%)Carbachol in guine pig ileumIC[107]
Morinda morindoides (Rubiaceae)Leaf extract (Aqueous)Ac, KCl in guinea pig ileumIC[46]
141 3-O-MethylquercetinRhamnus nakaharai (Rhamnaceae)Stem bark (not reported)Carbachol, H, KCl in guinea pig tracheaIC[108]
142 3,4′-DimethylquercetinArtemisia abrotanum (Asteraceae)Aerial part (MeOH 67%)Carbachol in guinea pig tracheaIC[109]
143 3,7-DimethylquercetinArtemisia abrotanum (Asteraceae)Aerial part (MeOH 67%)Carbachol in guinea pig tracheaIC[109]
144 IsoquercetinConyza filaginoides (Asteraceae)Leaf infusion [CHCl3:MeOH (1:1)]Spontaneous contraction in rat ileumIC[47]
Hedera helix (Araliaceae)Aerial parts (EtOH 30%)ACh in guinea pig ileumIC[80]
Drosera rotundifolia (Droseraceae)Aerial parts (EtOH 70%)Carbachol in guinea pig ileumIC[107]
Drosera madascariensis (Droseraceae)Leaf extract (EtOH 70%)Carbachol, H, PGF2 in guinea pig ileum and tracheaIC[106]
Psidium guajava (Myrtaceae)Leaf extract (MeOH)Peristalsis in guinea pig ileumIC[105]
145 Quercetin 3-α-rhamnoside or QuercitrosidePsidium guajava (Myrtaceae)Leaf extract (MeOH)Peristalsis in guinea pig ileumIC[105]
Morinda morindoides (Rubiaceae)Leaf extract (Aqueous)ACh, KCl in guinea pig ileumIC[46]
146 Quercetin 3-O-β-L-arabinosidePsidium guajava (Myrtaceae)Leaf extract (MeOH)Peristalsis in guinea pig ileumIC[105]
147 Quercetin 3-O-β-D-galactosidePsidium guajava (Myrtaceae)Leaf extract (MeOH)Peristalsis in guinea pig ileumIC[105]
Drosera madascariensis (Droseraceae)Leaf extract (EtOH 70%)Carbachol, H, PGF2 in guinea pig ileum and tracheaIC[106]
148 Quercetin 3-O-β-gentiobioside 3-O-β-D-Morinda morindoides (Rubiaceae)Leaf extract (Aqueous)ACh, KCl in guinea pig ileumIC[46]
GlucopyranosylquercetinDrosera rotundifolia (Droseraceae)Aerial parts (EtOH 70%)Carbachol in guinea pig ileumEO[107]
149 CentaureidinArtemisia abrotanum (Asteraceae)Aerial part (MeOH 67%)Carbachol in guinea pig tracheaIC[109]
150 Casticin or VitexicarpinArtemisia abrotanum (Asteraceae)Aerial part (MeOH 67%)Carbachol in guinea pig tracheaIC[109]
151 Prunetol or SophoricolGenista tridentata (Papilionaceae)Not reportedAC, electric field stimulation, 6-oxo PGE1 in guinea pig ileumIC[110]
152 Boeravinone EBoerhaavia diffusa (Nyctaginaceae)Root infusion (MeOH)ACh in guinea pig ileumIC[111]
153 4,6,11-trihydroxy-9-methoxy-10-methyl-6,12-dihydro-5,7-dioxatetraphen-12-oneBoerhaavia diffusa (Nyctaginaceae)Root infusion (MeOH)ACh in guinea pig ileumIC[111]
154 Boeravinone GBoerhaavia diffusa (Nyctaginaceae)Root infusion (MeOH)ACh in guinea pig ileumIC[111]
155 (2R,3S,2”R,3”R)-ManniflavononeGarcinia buchananii (Clusiaceae)Stem bark (EtOH 70%)Bay K 8644 in mouse ileumIC[112]
156 HyperosideHypericum perforatum (Hypericaceae)Aerial parts (EtOH 70%)KCl in rabbit jejunumIC[82]
157 ChrysoeriolArtemisia copa (Compositae)Aerial parts (Aqueous)KCl, PE, S in rat aortaE[98]
Aspalathus linearis (Fabaceae)Commercial (Aqueous)KCl in rabbit jejunumIC[102]
158 SpinacetinArtemisia copa (Compositae)Aerial parts (Aqueous)KCl, PE, S in rat aortaE[98]
159 Vicenin 2Perilla frutescens (Lamiaceae)Commercial (Aqueous)ACh, BaCl2 i rat ileumIC[113]
160 OrientinAspalathus linearis (Fabaceae)Commercial (Aqueous)KCl in rabbit jejunumIC[102]

Phenylmetanoids
161 Salicylic acid methyl etherBrickellia veronicifolia (Asteraceae)Aerial parts [CH2Cl2:MeOH (1:1)]Gastrointestinal motility test in mouseE[75]
162 O-Anisic acid or 6-Methoxysalicylic acidBrickellia veronicifolia (Asteraceae)Aerial parts [CH2Cl2:MeOH (1:1)]Gastrointestinal motility test in mouseE[75]
163 Protocatechuic acidHedera helix (Araliaceae)Aerial parts (EtOH 30%)ACh in guinea pig ileumIC[80]
164 Benzyl 2,5-dimethoxybenzoateBrickellia veronicifolia (Asteraceae)Aerial parts [CH2Cl2-MeOH (1:1)]Gastrointestinal motility test in mouseE[75]

Phenylethanoids
165 O-MethylbalsamideZanthoxylum hyemale (Rutaceae)Stem bark infusion (EtOH)ACh, BaCl2 in rat ileumIC[114]
166 (-)-TembamideZanthoxylum hyemale (Rutaceae)Stem bark infusion (EtOH)ACh, BaCl2 in rat ileumIC[114]
167 O-MethyltembamideZanthoxylum hyemale (Rutaceae)Steam bark infusion (EtOH)ACh, BaCl2 in rat ileumIC[114]

Phenylpropanoids
168 EugenolOcimum gratissimum (Lamiaceae)Not reportedACh, KCl in guinea pig ileumEO[34]
169 Rosemaric acid or Rosemary acid or trans-Rosmarinic acidThymus vulgaris (Lamiaceae)CommercialKCl in rat tracheaIC[100]
170 trans-Chlorogenic acidHedera helix (Araliaceae)Aerial parts (EtOH 30%)ACh in guinea pig ileumIC[80]
171 cis-Chlorogenic acidHedera helix (Araliaceae)Aerial parts (EtOH 30%)ACh in guinea pig ileumIC[80]
172 3,5-Dicaffeoylquininic acidHedera helix (Araliaceae)Aerial parts (EtOH 30%)ACh in guinea pig ileumIC[80]
173 VerbascosidePlantago lanceolata (Plantaginaceae)Aerial part infusion (EtOH 20%)ACh, BaCl2, H, KCl in guinea pig ileum and tracheaE[99]
174 Isoacteoside or IsoverbascosidePlantago lanceolata (Plantaginaceae)Aerial part infusion (EtOH 20%)ACh, BaCl2, H, KCl in guinea pig ileum and tracheaE[99]
175 Plantamajoside or Plantamoside or Purpureaside APlantago lanceolata (Plantaginaceae)Aerial part infusion (EtOH 20%)ACh, BaCl2, H, KCl in guinea pig ileum and tracheaE[99]
176 LavandulifoliosidePlantago lanceolata (Plantaginaceae)Aerial part infusion (EtOH 20%)ACh, BaCl2, H, KCl in guinea pig ileum and tracheaE[99]
177 EchinacosideCistanche tubulosa (Orobanchaceae)No reported (EtOH)KCl, PE in rat aortaIC[115]
178 Schisandrin A or Wuweizisu ASchisandra chinensis (Schisandraceae)AcademicSpontaneous contractions in rat colonIC[116]
179 Schisandrin B or Wuweizisu BSchisandra chinensis (Schisandraceae)Fruit decoction (Aqueous)ACh, KCl, S in guinea pig ileumIC[117]
180 Schisandrol BSchisandra chinensis (Schisandraceae)Fruit decoction (Aqueous)ACh, KCl, S in guinea pig ileumIC[117]

Stilbenoids
181 Aloifol II or Dendrophenol or MoscatilinNidema boothii (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH 1:1)]Spontaneous contraction in guinea pig ileumIC[118]
182 Batatasin IIINidema boothii (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH 1:1)]Spontaneous contraction in guinea pig ileumIC[118]
Scaphyglottis livida (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[119]
183 4-[2-(3-hydroxy-5-methoxyphenyl)ethyl]-2-methoxyphenolScaphyglottis livida (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[119]
184 GigantolNidema boothii (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH (1:1)]Spontaneous contraction in guinea pig ileumIC[118]
185 CoeloninScaphyglottis livida (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[119]
186 ErianthridinMaxillaria densa (Orchidaceae)Whole plant infusion [CHCl3-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[120]
187 EphemeranthoquinoneNidema boothii (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH (1:1)]Spontaneous contraction in guinea pig ileumIC[118]
188 NudolMaxillaria densa (Orchidaceae)Whole plant infusion [CHCl3-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[120]
189 3,4- dimethoxyphenanthrene-2,5-diolMaxillaria densa (Orchidaceae)Whole plant infusion [CHCl3-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[120]
190 DenthyrsininScaphyglottis livida (Orchidaceae)Whole plant infusion [CH2Cl2-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[119]
191 GymnopusinMaxillaria densa (Orchidaceae)Whole plant infusion [CHCl3-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[120]
192 Fimbriol AMaxillaria densa (Orchidaceae)Whole plant infusion [CHCl3-MeOH (1:1)]ACh, BaCl2, H in rat ileumIC[120]

Curcuminoid
193 (1E,5S,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3-oneCurcuma longa (Zingiberaceae)Macerated rhizome (EtOH 70%)ACh, BaCl2, CaCl2, H, KCl, O in guinea pig Ileum and rat uterusIC[121]

Benzofurans and Related
194 (+)-Vitisin CVitis spp. (Vitaceae)Stem infusion (MeOH)PE in rabbit aortaIC[122]
195 ButylphthalideLigusticum wallichii (Umbelliferae)Rhizome (hydrodistillation)CaCl2, KCl in rat aortaEO[123]
196 cis-ButylidenephthalideLigusticum wallichii (Umbelliferae)Rhizome (hydrodistillation)CaCl2, KCl in rat aortaEO[123]
197 Ligustilide A or cis-LigustilideLigusticum wallichii (Umbelliferae)Rhizome (hydrodistillation)CaCl2, KCl in rat aortaEO[123]
198 12-acetoxytremetoneHelichrysum italicum ssp. italicum (Asteraceae)Flowers (EtOH)ACh, BaCl2 in mouse ileumIC[124]
199 1-[(2R)-2-(3-hydroxyprop-1-en-2-yl)-2,3-dihydro-1-benzofuran-5-yl]ethan-1-oneHelichrysum italicum ssp. italicum (Asteraceae)Flowers (EtOH)ACh, BaCl2 in mouse ileumIC[124]

Alkaloids
200 IndicaxanthinOpuntia ficus indica (Cactaceae)Fruit pulp infusion (Aqueous)Carbachol, KCl in mouse ileumIC[125]
201 PapaverineDaucus carota (Apiaceae)Seed infusion (MeOH 90%)ACh, BaCl2, H, KCl, S, O in dog trachea, guinea pig, rabbit, rat ilea, rat uterusIC[126]
202 HigenamineNandina domestica (Berberidaceae)Fruit (Aqueous)ACh, H, KCl in guinea pig tracheaIC[127]
203 AtherosperminineFissistigma glaucescens (Annonaceae)Bark (MeOH)Carbachol, KCl, LTC4, PGF2α, U46619 in guinea pig tracheaIC[128]
204 (+)-Domestine or (+)-NanteninePlatycapnos spicata (Fumariaceae)Academic supplierBaCl2, CaCl2, KCl, PE, S in rat aorta and atriaIC[129]
205 10-MethylacridoneCitrus deliciosa (Rutaceae)Root juice (MeOH)Rabbit ileumIC[130]
206 Spermatheridine or liriodeninFissistigma glaucescens (Annonaceae)Leaf infusion (MeOH)Carbachol in canine tracheaIC[131]
207 Citpressine ICitrus deliciosa (Rutaceae)Root juice (MeOH)Rabbit ileumIC[130]
208 Jatrorhizine or NeprotineBerberis aristata (Berberidaceae)Institutional supplierACh, S, spontaneous contractions in rat ileumIC[132]
Coptis chinensis (Ranunculaceae)Rhizoma (EtOH 70%)ACh in guinea pig ileumIC[133]
209 CoptisineCoptis chinensis (Ranunculaceae)Rhizoma (EtOH 70%)ACh in guinea pig ileumIC[133]
210 Escholine or ThalictrineMahonia aquifolium (Berberidaceas)Cortex and fruit infusionKCl, PE in rat aortaIC[134]
211 (+)-IsothebaineMahonia aquifolium (Berberidaceas)Cortex and fruit infusionKCl, PE in rat aortaIC[134]
212 (+)-CorytuberineMahonia aquifolium (Berberidaceas)Cortex and fruit infusionKCl, PE in rat aortaIC[134]
213 (+)-Isocorydine or LuteanineMahonia aquifolium (Berberidaceas)Cortex and fruit infusionKCl, PE in rat aortaIC[134]
214 (+)-Chelidonine or StylophorineChelidonium majus (Papaveraceae)Commercial supplierBaCl2, carbachol in guinea pig ileumIC[135]
215 (-)-8 beta-(4′-hydroxybenzyl)-2,3-dimethoxyberbin-10-olAristolochia constricta (Aristolochiaceae)Aerial part infusion (MeOH)ACh, electrical contraction, H in guinea pig ileumIC[136]
216 3-O-methylconstrictosineAristolochia constricta (Aristolochiaceae)Aerial part infusion (MeOH)ACh, electrical contraction, H in guinea pig ileumIC[136]
217 3,5-di-O-methylconstrictosineAristolochia constricta (Aristolochiaceae)Aerial part infusion (MeOH)ACh, electrical contraction, H in guinea pig ileumIC[136]
218 5,6-dihydro-3,5-di-O-methylconstrictosineAristolochia constricta (Aristolochiaceae)Aerial part infusion (MeOH)ACh, electrical contraction, H in guinea pig ileumIC[136]
219 5,6-dihydroconstrictosineAristolochia constricta (Aristolochiaceae)Aerial part infusion (MeOH)ACh, electrical contraction, H in guinea pig ileumIC[136]
220 ConstrictosineAristolochia constricta (Aristolochiaceae)Aerial part infusion (MeOH)ACh, electrical contraction, H in guinea pig ileumIC[136]
221 IsojuripidineSolanum asterophorum (Solanaceae)Leaf infusion (MeOH)ACh, CaCl2, H in guinea pig ileumIC[137]
222 SarcodineSarcocca saligna (Buxaceae)Whole plant (MeOH)ACh, KCl in guinea pig ileum, rat stomach fundus, rabbit jejunumIC[138]
223 Saracorine or SarcorineSarcococca saligna (Buxaceae)Whole plant infusion (MeOH)ACh, KCl in rabbit jejunumIC[139]
224 SaracocineSarcocca saligna (Buxaceae)Whole plant (MeOH)ACh, KCl in guinea pig ileum, rat stomach fundus, rabbit jejunumIC[138]
225 Alkaloid CSarcocca saligna (Buxaceae)Whole plant (MeOH)ACh, KCl in guinea pig ileum, rat stomach fundus, rabbit jejunumIC[138]
226 (-)-Pachyaximine ASarcococca saligna (Buxaceae)Whole plant infusion (MeOH)ACh, KCl in rabbit jejunum, KClIC[139]
227 (-)-(R)-Geibalansine or (-)-R-GeilbalansineZanthoxylum hyemale (Rutaceae)Stem bark infusion (EtOH)ACh, BaCl2 in rat ileumIC[114]
228 HyemalineZanthoxylum hyemale (Rutaceae)Stem bark infusion (EtOH)ACh, BaCl2 in rat ileumIC[114]
229 TheophyllineFissistigma glaucescens (Annonaceae)Leaf infusion (MeOH)Carbachol in canine tracheaIC[131]
230 Carboxyscotangamine AScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]
231 Scotanamine AScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]
232 PiperinePiper nigrum (Piperaceae)Fruit (EtOH)Ileum loop in miceIC[141]

Amines
233 Scotanamine BScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[123]
234 Scotanamine CScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]
235 Scotanamine DScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]
236 N1-Caffeoyl-N3-dihydrocaffeoylspermidineScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]
237 N1, N10-Bis(dihydrocaffeoyl)spermidineScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]
238 CaffeoylputrescineScopolia tangutica (Solanaceae)Root (95% EtOH)Carbachol in Chinese hamster ovarian cellIC[140]

Isothiocyanates
239 Redskin or SenfoelCruciferous vegetables (Brassicaceae)Commercial sourceACh, electrical contraction in mouse ileumIC[142]

Alcohols
240 (3E)-4-(3,4-dimethoxyphenyl)but-3-en-1-olZingiber cassumunar (Zingiberaceae)Chemically synthesizedO in rat uterusIC[143]

Ketones
241 2-DecanoneRuta chalepensis (Rutaceae)Leaf (EtOH 70%)KCl in rat ileumE[144]
242 2-UndecanoneRuta chalepensis (Rutaceae)Leaf (EtOH 70%)KCl in rat ileumE[144]
243 2-TridecanoneRuta chalepensis (Rutaceae)Leaf (EtOH 70%)KCl in rat ileumE[144]
244 LatifoloneFerula heuffelii (Apiaceae)Underground part (CHCl3)ACh, KCl in rat ileumIC[85]
245 DshamironeFerula heuffelii (Apiaceae)Underground part (CHCl3)ACh, KCl in rat ileumIC[85]

Phenolic compounds
246 6-(4-hydroxy-3-methoxyphenyl)-hexanonic acid (HMPHA)Pycnocycla spinosa (Umbelliferae)Aerial parts (MeOH)KCl in rat ileumIC[145]
247 IsovanillinPycnocycla spinosa (Umbelliferae)Aerial parts (MeOH)KCl in rat ileumIC[146]
248 Iso-acetovanillonPycnocycla spinosa (Umbelliferae)Aerial parts (MeOH)KCl in rat ileumIC[146]

IC = isolated compound, E = extract, EO = essential oil, ACh = acetylcholine, O = oxytocin, PMA = β-Phenylethyl amsine, PGF = Prostaglandin F2α, H = histamine, S = serotonin.

Some advantages of performing ex vivo experiments are as follows: (i) different substances can be evaluated in fresh tissues without absorption factors, metabolic excretion or interference due to nerve reflexes; (ii) it is possible to quantify the effect produced by a precisely determined drug; and (iii) it is easier to obtain dose-effect curves, such as the smooth muscle where the contraction obtained under the influence of a spasm or in tissue homogenates is measured by determination of the enzyme activities [172, 174].

5.2. Guinea Pig Ileum and Rat Stomach

The ileum is removed and cut in strips of approximately 2 cm long and then placed in a bath filled with an isotonic solution as mentioned earlier. Electrophysiological studies are performed by graphically recording the contractions with the aid of a transducer, which is calibrated 30 min before the treatment begins. A range of 0.01 to 0.03 μM is generally used to determine dose response curves of the antispasmodic substance [175].

In rats, the stomach is removed and the corpus and fundus are cut in strips of approximately 5 mm x 15 mm and placed on a prewarmed warm solution as mentioned before.

5.3. Compounds Used to Elicit a Spasmodic Activity

The main compounds used are acetylcholine, atropine, BaCl2, carbachol, histamine, KCl, and serotonin.

Acetylcholine is a postganglionic neurotransmitter in the parasympathetic neurons that innervate the intestine. The response to acetylcholine is regulated by activation of the two types of muscarinic receptors: M2 and M3 [176]. The activation of these receptors causes contractions by increasing the intracellular concentration of Ca2+ via IP3 [176]. Atropine is a competitive reversible antagonist of muscarinic acetylcholine receptors M1, M2, M3, M4, and M5.

Different substances are used to produce contractions. For example, BaCl2 induces contractions by mobilizing membrane-bound Ca2+ [177], carbachol is a cholinomimetic drug (cholinergic agonist) that binds and activates acetylcholine receptors [178], histamine acts by either accelerating the release of acetylcholine or interacting supra-additively with the acetylcholine at the smooth muscle [179], whereas KCl increases the voltage-operated Ca2+ channel activity by increasing intracellular free Ca2+ in smooth muscle [180]. Serotonin is also an important neurotransmitter mainly stored in the digestive tract, affecting the secretory and motor activities. At high concentrations, it acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors [181, 182].

6. Antispasmodic Activity of Natural Compounds

Compounds isolated from terrestrial plants have shown the ability to function as antispasmodic compounds. The chemical group with the highest number of members of antispasmodic compounds is the monoterpenoid group (41 compounds) followed by flavonoids (35 compounds), alkaloids (with 33 compounds), and triterpenes with 31 (Figure 1). Although we summarize in Table 3 248 compounds, in most of the cases the mechanism behind their activity has not been elucidated.

7. Mutagenicity

Studies related to the mutagenicity of antispasmodics are very scarce. This topic has been underestimated when testing the bioactivities of ethnomedicinal plants. Probably the most useful method to determine the mutagenicity of natural products or plant extracts is the Ames method [183]. This test is based on the rate of mutations detected in genetically modified strains of Salmonella typhimurium. Moreover, this test has also been developed to detect mutagenicity of metabolized compounds in the liver. In this situation, a mixture of liver enzymes (S9 microsomal fraction) is used to mimic the metabolites that will be produced in the liver [184].

Few studies have been performed to determine the mutagenicity of natural products with antispasmodic activity. For example, the flavonoids quercetin and luteolin were tested using the Ames method and the appearance of point mutations in four of the tested bacterial strains was shown [185]. In another study, the extracts of the plants Brickellia veronicaefolia, Gnaphalium sp., Poliomintha longiflora, and Valeriana procera were studied. Compounds isolated from these plants are listed as antispasmodic compounds (Table 3). Results of the mutagenicity test indicated that Gnaphalium sp., Poliomintha longiflora (used in the Mexican cuisine and as a traditional medicine), and Valeriana procera induced mutagenesis in the tested bacterial strain [186].

8. Chemical Similarities between Natural and Synthetic Antispasmodic Compounds

To determine whether or not there is an analogy between synthetic (Table 4) and natural antispasmodic compounds, the structures of both groups were compared. Results showed that no similarities were found except for alkaloids, amines, and amino acids.


Synthetic compoundReceptor targetedMain use

Alkaloids
ChlorzoxazonePrevents release of histamineMuscular spasm
PancuroniumNicotinic acetylcholineMuscle relaxant
RiluzoleSodium channelsAmyotrophic lateral sclerosis
RocuroniumAntagonist of neuromuscular junctionMuscle relaxant and anaesthesia
Tizanidineα2 adrenergic agonistMuscle relaxant
VecuroniumNicotinic acetylcholineMuscle relaxant and anaesthesia

Curcuminoids
AtracuriumNicotinic acetylcholineMuscle relaxant and anaesthesia
CisatracuriumNicotinic acetylcholineMuscle relaxant and anaesthesia
MivacuriumNicotinic acetylcholineMuscle relaxant and anaesthesia

Methylpropanoid
DiazepamAnxiety, alcohol withdrawal syndrome, muscle spasms, seizures, and restless legs syndrome
PrograbideEpilepsy
OrphenadrineSkeletal muscle relaxant that is used for the treatment of acute muscle aches, pain, or spasms.

Phenylpropanoids
BaclofenSpinal cord injury, cerebral palsy, and multiple sclerosis
IdrocilamidePrevents release of intracellular Ca2+Skeletal muscle relaxant and muscular pain

One of the main differences is that commercial alkaloids are methylated in their nitrogen to make them positive, increasing their solubilities because of salt formation. In contrast, natural products have no positive nitrogen, rendering the molecule neutral and pH dependent. Thus, the compound may or may not be protonated, resulting in a change in its solubility and consequently a change on the targeting tissues.

The comparison can perhaps be focused on the distribution of charges rather than by functional groups or families of compounds, emphasizing the electron distribution. For example, a physical characterization such as the heat of formation, the surface electrostatic potential, the molecular weight, the surface tension, the refractive index, the lipophilicity, and others has been used to characterize the structure-activity relationship of alkaloids extracted from the Amaryllidaceae family [187]. These alkaloids were selected because of their ability to inhibit the effect of the acetylcholinesterase enzyme.

Of special interest is the natural compound salvinorin A isolated from the Mexican hallucinogenic Salvia divinorum (Lamiaceae) used in the traditional medicine as an antidiarrheal. It has been reported that this compound inhibited the intestinal motility through the activation of other receptors such as κ-opioid receptors (KORs). Upon inflammation of the gut, the cannabinoid C, B1, and KOR receptors are upregulated. It appears that salvinorin A interacts in the cross-talk between these receptors with a reduction of the inflammation as demonstrated in murine and guinea pig models [188, 189].

Analysis of the similarities between synthetic and natural antispasmodic structures is depicted in Table 5.


SyntheticNatural





9. Conclusions

A large number of natural products with antispasmodic activities have been reported. Although the use of plants in traditional medicine is still relevant, it is necessary to perform new studies to elucidate the mechanism of action of antispasmodics. Moreover, more information about cytotoxicity and mutagenesis should be explored to ensure that these compounds are safe for consumption. The findings of this study corroborated the need for safety studies on plants extensively used for primary health care in countries such as Mexico. Such studies must be carried out before continuing with the widespread use of some species, which may provoke long-term and irreversible damage.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors thank Marilyn Robertson for helpful discussion.

Supplementary Materials

This file contains the structures of the compounds described in the main text. (Supplementary Materials)

References

  1. D. M. Warburton, “Behavioral effects of central and peripheral changes in acetylcholine systems,” Journal of Comparative and Physiological Psychology, vol. 68, no. 1, pp. 56–64, 1969. View at: Publisher Site | Google Scholar
  2. F. Anthony Lai, H. P. Erickson, E. Rousseau, Q.-Y. Liu, and G. Meissner, “Purification and reconstitution of the calcium release channel from skeletal muscle,” Nature, vol. 331, no. 6154, pp. 315–319, 1988. View at: Publisher Site | Google Scholar
  3. A. Apostolidis, A. Haferkamp, and K. R. Aoki, “Understanding the Role of Botulinum Toxin A in the Treatment of the Overactive Bladder-More than Just Muscle Relaxation,” European Urology, Supplements, vol. 5, no. 11, pp. 670–678, 2006. View at: Publisher Site | Google Scholar
  4. O. Rossetto, M. Scorzeto, A. Megighian, and C. Montecucco, “Tetanus neurotoxin,” Toxicon, vol. 66, pp. 59–63, 2013. View at: Publisher Site | Google Scholar
  5. A. Marino, V. Valveri, C. Muià et al., “Cytotoxicity of the nematocyst venom from the sea anemone Aiptasia mutabilis,” Comparative Biochemistry and Physiology - C Toxicology and Pharmacology, vol. 139, no. 4, pp. 295–301, 2004. View at: Publisher Site | Google Scholar
  6. R. J. A. Hughes, J. A. Angus, K. D. Winkel, and C. E. Wright, “A pharmacological investigation of the venom extract of the Australian box jellyfish, Chironex fleckeri, in cardiac and vascular tissues,” Toxicology Letters, vol. 209, no. 1, pp. 11–20, 2012. View at: Publisher Site | Google Scholar
  7. T. D. Nguyen-Huu, C. Mattei, P. J. Wen et al., “Ciguatoxin-induced catecholamine secretion in bovine chromaffin cells: Mechanism of action and reversible inhibition by brevenal,” Toxicon, vol. 56, no. 5, pp. 792–796, 2010. View at: Publisher Site | Google Scholar
  8. M. E. P. Junqueira, L. Z. Grund, N. M. Orii et al., “Analysis of the inflammatory reaction induced by the catfish (Cathorops spixii) venoms,” Toxicon, vol. 49, no. 7, pp. 909–919, 2007. View at: Publisher Site | Google Scholar
  9. J. Sawynok, “GABAergic mechanisms of analgesia: an update,” Pharmacology Biochemistry & Behavior, vol. 26, no. 2, pp. 463–474, 1987. View at: Publisher Site | Google Scholar
  10. D. Quan and A.-M. Ruha, “Priapism associated with Latrodectus mactans envenomation,” The American Journal of Emergency Medicine, vol. 27, no. 6, pp. 759–e2, 2009. View at: Publisher Site | Google Scholar
  11. N. Ahmed, M. Pinkham, and D. A. Warrell, “Symptom in search of a toxin: Muscle spasms following bites by Old World tarantula spiders (Lampropelma nigerrimum, Pterinochilus murinus, Poecilotheria regalis) with review,” QJM: An International Journal of Medicine, vol. 102, no. 12, pp. 851–857, 2009. View at: Publisher Site | Google Scholar
  12. S. Liang, “An overview of peptide toxins from the venom of the Chinese bird spider Selenocosmia huwena Wang [=Ornithoctonus huwena (Wang)],” Toxicon, vol. 43, no. 5, pp. 575–585, 2004. View at: Publisher Site | Google Scholar
  13. K. J. Swartz, “Tarantula toxins interacting with voltage sensors in potassium channels,” Toxicon, vol. 49, no. 2, pp. 213–230, 2007. View at: Publisher Site | Google Scholar
  14. B. A. Cromer and P. McIntyre, “Painful toxins acting at TRPV1,” Toxicon, vol. 51, no. 2, pp. 163–173, 2008. View at: Publisher Site | Google Scholar
  15. Z.-F. Chai, M.-M. Zhu, Z.-T. Bai et al., “Chinese-scorpion (Buthus martensi Karsch) toxin BmK αIV, a novel modulator of sodium channels: From genomic organization to functional analysis,” Biochemical Journal, vol. 399, no. 3, pp. 445–453, 2006. View at: Publisher Site | Google Scholar
  16. C. Bon, “Synergism of the two subunits of crotoxin,” Toxicon, vol. 20, no. 1, pp. 105–109, 1982. View at: Publisher Site | Google Scholar
  17. C. C. Câmara, N. R. F. Nascimento, C. L. Macêdo-Filho, F. B. S. Almeida, and M. C. Fonteles, “Antispasmodic Effect of the Essential Oil of Plectranthus barbatus and some Major Constituents on the Guinea-Pig Ileum,” Planta Medica, vol. 69, no. 12, pp. 1080–1085, 2003. View at: Publisher Site | Google Scholar
  18. H. Ponce-Monter, E. Fernández-Martínez, M. I. Ortiz et al., “Spasmolytic and anti-inflammatory effects of Aloysia triphylla and citral, in vitro and in vivo studies,” Journal of Smooth Muscle Research, vol. 46, no. 6, pp. 309–319, 2010. View at: Publisher Site | Google Scholar
  19. R. C. Devi, S. M. Sim, and R. Ismail, “Spasmolytic effect of citral and extracts of Cymbopogon citratus on isolated rabbit ileum,” Journal of Smooth Muscle Research, vol. 47, no. 5, pp. 143–156, 2011. View at: Publisher Site | Google Scholar
  20. H. Sadraei, A. Ghannadi, and K. Malekshahi, “Relaxant effect of essential oil of Melissa officinalis and citral on rat ileum contractions,” Fitoterapia, vol. 74, no. 5, pp. 445–452, 2003. View at: Publisher Site | Google Scholar
  21. A. Karim, M. Berrabah, H. Mekhfi et al., “Effect of essential oil of Anthemis mauritiana Maire & Sennen flowers on intestinal smooth muscle contractility,” Journal of Smooth Muscle Research, vol. 46, no. 1, pp. 65–75, 2010. View at: Publisher Site | Google Scholar
  22. A. H. Gilani, A. J. Shah, A. Zubair et al., “Chemical composition and mechanisms underlying the spasmolytic and bronchodilatory properties of the essential oil of Nepeta cataria L.,” Journal of Ethnopharmacology, vol. 121, no. 3, pp. 405–411, 2009. View at: Publisher Site | Google Scholar
  23. H. Sadraei, G. Asghari, and S. Emami, “Inhibitory effect of Rosa damascena Mill flower essential oil, geraniol and citronellol on rat ileum contraction,” Research in Pharmaceutical Sciences, vol. 8, no. 1, pp. 17–23, 2013. View at: Google Scholar
  24. A. Riyazi, A. Hensel, K. Bauer, N. Geißler, S. Schaaf, and E. J. Verspohl, “The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum,” Planta Medica, vol. 73, no. 4, pp. 355–362, 2007. View at: Publisher Site | Google Scholar
  25. L. Pinho-Da-Silva, P. V. Mendes-Maia, T. M. Do Nascimento Garcia et al., “Croton sonderianus essential oil samples distinctly affect rat airway smooth muscle,” Phytomedicine, vol. 17, no. 10, pp. 721–725, 2010. View at: Publisher Site | Google Scholar
  26. O. Prakash, V. K. Kasana, A. K. Pant, A. Zafar, S. K. Hore, and C. S. Mathela, “Phytochemical composition of essential oil from seeds of Zingiber Roseum Rosc. and its antispasmodic activity in rat duodenum,” Journal of Ethnopharmacology, vol. 106, no. 3, pp. 344–347, 2006. View at: Publisher Site | Google Scholar
  27. D. P. De Sousa, G. A. S. Júnior, L. N. Andrade et al., “Structure and spasmolytic activity relationships of monoterpene analogues found in many aromatic plants,” Section C Journal of Biosciences, vol. 63, no. 11-12, pp. 808–812, 2008. View at: Google Scholar
  28. H. Sadraei, G. Asghari, and F. Kasiri, “Comparison of antispasmodic effects of Dracocephalum kotschyi essential oil, limonene and α-terpineol,” Research in Pharmaceutical Sciences, vol. 10, no. 2, pp. 109–116, 2015. View at: Google Scholar
  29. A. Astudillo, E. Hong, R. Bye, and A. Navarrete, “Antispasmodic activity of extracts and compounds of Acalypha phleoides Cav.,” Phytotherapy Research, vol. 18, no. 2, pp. 102–106, 2004. View at: Publisher Site | Google Scholar
  30. N. Wienkötter, D. Höpner, U. Schütte et al., “The effect of nigellone and thymoquinone on inhibiting trachea contraction and mucociliary clearance,” Planta Medica, vol. 74, no. 2, pp. 105–108, 2008. View at: Publisher Site | Google Scholar
  31. S. V. Brankovic, D. V. Kitic, M. M. Radenkovic, S. M. Veljkovic, and T. D. Golubovic, “Calcium blocking activity as a mechanism of the spasmolytic effect of the essential oil of Calamintha glandulosa Silic on the isolated rat ileum,” General Physiology and Biophysics, vol. 28, pp. 174–178, 2009. View at: Publisher Site | Google Scholar
  32. K. Heimes, F. Hauk, and E. J. Verspohl, “Mode of action of peppermint oil and (-)-menthol with respect to 5-HT3 receptor subtypes: Binding studies, cation uptake by receptor channels and contraction of isolated rat ileum,” Phytotherapy Research, vol. 25, no. 5, pp. 702–708, 2011. View at: Publisher Site | Google Scholar
  33. H. Ponce-Monter, M. G. Campos, S. Pérez et al., “Chemical composition and antispasmodic effect of Casimiroa pringlei essential oil on rat uterus,” Fitoterapia, vol. 79, no. 6, pp. 446–450, 2008. View at: Publisher Site | Google Scholar
  34. S. V. F. Madeira, M. Rabelo, P. M. G. Soares et al., “Temporal variation of chemical composition and relaxant action of the essential oil of Ocimum gratissimum L. (Labiatae) on guinea-pig ileum,” Phytomedicine, vol. 12, no. 6-7, pp. 506–509, 2005. View at: Publisher Site | Google Scholar
  35. I. Rivero-Cruz, G. Duarte, A. Navarrete, R. Bye, E. Linares, and R. Mata, “Chemical composition and antimicrobial and spasmolytic properties of poliomintha longiflora and lippia graveolens essential oils,” Journal of Food Science, vol. 76, no. 2, pp. C309–C317, 2011. View at: Publisher Site | Google Scholar
  36. S. I. H. Taqvi, A. J. Shah, and A. H. Gilani, “Insight into the possible mechanism of antidiarrheal and antispasmodic activities of piperine,” Pharmaceutical Biology, vol. 47, no. 8, pp. 660–664, 2009. View at: Publisher Site | Google Scholar
  37. F. Begrow, J. Engelbertz, B. Feistel, R. Lehnfeld, K. Bauer, and E. J. Verspohl, “Impact of Thymol in thyme extracts on their antispasmodic action and ciliary clearance,” Planta Medica, vol. 76, no. 4, pp. 311–318, 2010. View at: Publisher Site | Google Scholar
  38. T. Görnemann, R. Nayal, H. H. Pertz, and M. F. Melzig, “Antispasmodic activity of essential oil from Lippia dulcis Trev.,” Journal of Ethnopharmacology, vol. 117, no. 1, pp. 166–169, 2008. View at: Publisher Site | Google Scholar
  39. T. A. Abere, P. E. Okoto, and F. O. Agoreyo, “Antidiarrhoea and toxicological evaluation of the leaf extract of Dissotis rotundifolia triana (Melastomataceae),” BMC Complementary and Alternative Medicine, vol. 10, article 71, 2010. View at: Publisher Site | Google Scholar
  40. F. J. B. Lima, T. S. Brito, W. B. S. Freire et al., “The essential oil of Eucalyptus tereticornis, and its constituents α- And β-pinene, potentiate acetylcholine-induced contractions in isolated rat trachea,” Fitoterapia, vol. 81, no. 6, pp. 649–655, 2010. View at: Publisher Site | Google Scholar
  41. H. Sadraei, G. R. Asghari, V. Hajhashemi, A. Kolagar, and M. Ebrahimi, “Spasmolytic activity of essential oil and various extracts of Ferula gummosa Boiss. on ileum contractions,” Phytomedicine, vol. 8, no. 5, pp. 370–376, 2001. View at: Publisher Site | Google Scholar
  42. T. M. S. Da Silva, B. A. Da Silva, and R. Mukherjee, “The monoterpene alkaloid cantleyine from Strychnos trinervis root and its spasmolytic properties,” Phytomedicine, vol. 6, no. 3, pp. 169–176, 1999. View at: Publisher Site | Google Scholar
  43. A. V. Ortiz De Urbina, M. L. Martin, B. Fernandez, L. San Roman, and L. Cubillo, “In vitro antispasmodic activity of peracetylated penstemonoside, aucubin and catalpol,” Planta Medica, vol. 60, no. 6, pp. 512–515, 1994. View at: Publisher Site | Google Scholar
  44. M. F. Cometa, L. Parisi, M. Palmery, A. Meneguz, and L. Tomassini, “In vitro relaxant and spasmolytic effects of constituents from Viburnum prunifolium and HPLC quantification of the bioactive isolated iridoids,” Journal of Ethnopharmacology, vol. 123, no. 2, pp. 201–207, 2009. View at: Publisher Site | Google Scholar
  45. B. Hazelhoff, T. M. Malingre, and D. K. F. Meijer, “Antispasmodic effects of valeriana compounds: An in-vivo and in-vitro study on the guinea-pig ileum,” Archives Internationales de Pharmacodynamie et de Thérapie, vol. 257, no. 2, pp. 274–287, 1982. View at: Google Scholar
  46. R. K. Cimanga, P. N. K. Mukenyi, O. K. Kambu et al., “The spasmolytic activity of extracts and some isolated compounds from the leaves of Morinda morindoides (Baker) Milne-Redh. (Rubiaceae),” Journal of Ethnopharmacology, vol. 127, no. 2, pp. 215–220, 2010. View at: Publisher Site | Google Scholar
  47. R. Mata, A. Rojas, L. Acevedo et al., “Smooth muscle relaxing flavonoids and terpenoids from Conyza filaginoides,” Planta Medica, vol. 63, no. 1, pp. 31–35, 1997. View at: Publisher Site | Google Scholar
  48. V. Leonhardt, J. H. Leal-Cardoso, S. Lahlou et al., “Antispasmodic effects of essential oil of Pterodon polygalaeflorus and its main constituent β-caryophyllene on rat isolated ileum,” Fundamental & Clinical Pharmacology, vol. 24, no. 6, pp. 749–758, 2010. View at: Publisher Site | Google Scholar
  49. A. Nasiri, A. Holth, and L. Bjork, “Effects of the sesquiterpene capsidiol on isolated guinea-pig ileum and trachea, and on prostaglandin synthesis in vitro,” Planta Medica, vol. 59, no. 3, pp. 203–206, 1993. View at: Publisher Site | Google Scholar
  50. W.-C. Ko, C.-B. Lei, Y.-L. Lin, and C.-F. Chen, “Mechanisms of relaxant action of S-petasin and S-isopetasin, sesquiterpenes of Petasites formosanus, in isolated guinea pig trachea,” Planta Medica, vol. 67, no. 3, pp. 224–229, 2001. View at: Publisher Site | Google Scholar
  51. O. Maschi, E. Dal Cero, G. V. Galli, D. Caruso, E. Bosisio, and M. Dell'Agli, “Inhibition of human cAMP-phosphodiesterase as a mechanism of the spasmolytic effect of Matricaria recutita L.,” Journal of Agricultural and Food Chemistry, vol. 56, no. 13, pp. 5015–5020, 2008. View at: Publisher Site | Google Scholar
  52. N. Perez-Hernandez, H. Ponce-Monter, J. A. Medina, and P. Joseph-Nathan, “Spasmolytic effect of constituents from Lepechinia caulescens on rat uterus,” Journal of Ethnopharmacology, vol. 115, no. 1, pp. 30–35, 2008. View at: Publisher Site | Google Scholar
  53. F. Emendörfer, F. Bellato, V. F. Noldin et al., “Antispasmodic activity of fractions and cynaropicrin from Cynara scolymus on guinea-pig ileum,” Biological & Pharmaceutical Bulletin, vol. 28, no. 5, pp. 902–904, 2005. View at: Publisher Site | Google Scholar
  54. S. Ammar, H. Edziri, M. A. Mahjoub, R. Chatter, A. Bouraoui, and Z. Mighri, “Spasmolytic and anti-inflammatory effects of constituents from Hertia cheirifolia,” Phytomedicine, vol. 16, no. 12, pp. 1156–1161, 2009. View at: Publisher Site | Google Scholar
  55. K. Kar, V. N. Puri, G. K. Patnaik et al., “Spasmolytic constituents of Cedrus deodara (Roxb.) Loud: Pharmacological evaluation of himachalol,” Journal of Pharmaceutical Sciences, vol. 64, no. 2, pp. 258–262, 1975. View at: Publisher Site | Google Scholar
  56. U. Pongprayoon, P. Baeckstrom, U. Jacobsson, M. Lindstrom, and L. Bohlin, “Antispasmodic activity of β-damascenone and E-phytol isolated from Ipomoea pes-caprae,” Planta Medica, vol. 58, no. 1, pp. 19–21, 1992. View at: Publisher Site | Google Scholar
  57. G. M. Natividad, K. J. Broadley, B. Kariuki, E. J. Kidd, W. R. Ford, and C. Simons, “Actions of Artemisia vulgaris extracts and isolated sesquiterpene lactones against receptors mediating contraction of guinea pig ileum and trachea,” Journal of Ethnopharmacology, vol. 137, no. 1, pp. 808–816, 2011. View at: Publisher Site | Google Scholar
  58. H. Guo, J. Zhang, W. Gao, Z. Qu, and C. Liu, “Gastrointestinal effect of methanol extract of Radix Aucklandiae and selected active substances on the transit activity of rat isolated intestinal strips,” Pharmaceutical Biology, vol. 52, no. 9, pp. 1141–1149, 2014. View at: Publisher Site | Google Scholar
  59. H. Ponce-Monter, S. Perez, M. A. Zavala et al., “Relaxant effect of xanthomicrol and 3α-angeloyloxy-2α-hydroxy- 13,14Z-dehydrocativic acid from Brickellia paniculata on rat uterus,” Biological & Pharmaceutical Bulletin, vol. 29, no. 7, pp. 1501–1503, 2006. View at: Publisher Site | Google Scholar
  60. D. Rigano, G. Aviello, M. Bruno et al., “Antispasmodic effects and structure-activity relationships of labdane diterpenoids from Marrubium globosum ssp. libanoticum,” Journal of Natural Products, vol. 72, no. 8, pp. 1477–1481, 2009. View at: Publisher Site | Google Scholar
  61. S. El Bardai, N. Morel, M. Wibo et al., “The vasorelaxant activity of marrubenol and marrubiin from Marrubium vulgare,” Planta Medica, vol. 69, no. 1, pp. 75–77, 2003. View at: Publisher Site | Google Scholar
  62. L. A. Aguiar, R. S. Porto, S. Lahlou et al., “Antispasmodic effects of a new kaurene diterpene isolated from Croton argyrophylloides on rat airway smooth muscle,” Journal of Pharmacy and Pharmacology, vol. 64, no. 8, pp. 1155–1164, 2012. View at: Publisher Site | Google Scholar
  63. S. R. Ambrosio, C. R. Tirapelli, D. Bonaventura, A. M. De Oliveira, and F. B. Da Costa, “Pimarane diterpene from Viguiera arenaria (Asteraceae) inhibit rat carotid contraction,” Fitoterapia, vol. 73, no. 6, pp. 484–489, 2002. View at: Publisher Site | Google Scholar
  64. L. van Puyvelde, R. Lefebvre, P. Mugabo, N. De Kimpe, and N. Schamp, “Active principles of Tetradenia riparia; II. Antispasmodic activity of 8 (14),15-sandaracopimaradiene-7α,18-diol,” Planta Medica, vol. 53, no. 2, pp. 156–158, 1987. View at: Publisher Site | Google Scholar
  65. G. Romussi, G. Ciarallo, A. Bisio et al., “A new diterpenoid with antispasmodic activity from Salvia cinnabarina,” Planta Medica, vol. 67, no. 2, pp. 153–155, 2001. View at: Publisher Site | Google Scholar
  66. A. Zamilpa, J. Tortoriello, V. Navarro, G. Delgado, and L. Alvarez, “Antispasmodic and antimicrobial diterpenic acids from Viguiera hypargyrea roots,” Planta Medica, vol. 68, no. 3, pp. 281–283, 2002. View at: Publisher Site | Google Scholar
  67. R. F. Santos, I. R. R. Martins, R. A. Travassos et al., “Ent-7α-acetoxytrachyloban-18-oic acid and ent-7α- hydroxytrachyloban-18-oic acid from Xylopia langsdorfiana A. St-Hil. & Tul. modulate K + and Ca 2+ channels to reduce cytosolic calcium concentration on guinea pig ileum,” European Journal of Pharmacology, vol. 678, no. 1-3, pp. 39–47, 2012. View at: Google Scholar
  68. J. Hu, W.-Y. Gao, L. Ma, S.-L. Man, L.-Q. Huang, and C.-X. Liu, “Activation of M3 muscarinic receptor and Ca2+ influx by crude fraction from Crotonis Fructus in isolated rabbit jejunum,” Journal of Ethnopharmacology, vol. 139, no. 1, pp. 136–141, 2012. View at: Publisher Site | Google Scholar
  69. M. Ghanadian, H. Sadraei, S. Yousuf, G. Asghari, M. I. Choudhary, and M. Jahed, “New diterpene polyester and phenolic compounds from Pycnocycla spinosa Decne. Ex Boiss with relaxant effects on KCl-induced contraction in rat ileum,” Phytochemistry Letters, vol. 7, no. 1, pp. 57–61, 2014. View at: Publisher Site | Google Scholar
  70. E. Barile, R. Capasso, A. A. Izzo, V. Lanzotti, S. E. Sajjadi, and B. Zolfaghari, “Structure-activity relationships for saponins from Allium hirtifolium and Allium elburzense and their antispasmodic activity,” Planta Medica, vol. 71, no. 11, pp. 1010–1018, 2005. View at: Publisher Site | Google Scholar
  71. S. Begum, I. Sultana, B. S. Siddiqui, F. Shaheen, and A. H. Gilani, “Structure and spasmolytic activity of eucalyptanoic acid from Eucalyptus camaldulensis var. obtusa and synthesis of its active derivative from oleanolic acid,” Journal of Natural Products, vol. 65, no. 12, pp. 1939–1941, 2002. View at: Publisher Site | Google Scholar
  72. G. Corea, E. Fattorusso, V. Lanzotti, R. Capasso, and A. A. Izzo, “Antispasmodic saponins from bulbs of red onion, Allium cepa L. var. Tropea,” Journal of Agricultural and Food Chemistry, vol. 53, no. 4, pp. 935–940, 2005. View at: Publisher Site | Google Scholar
  73. M. González-Cortazar, J. Tortoriello, and L. Alvarez, “Norsecofriedelanes as spasmolytics, advances of structure-activity relationships,” Planta Medica, vol. 71, no. 8, pp. 711–716, 2005. View at: Publisher Site | Google Scholar
  74. A. Y. S. Gomes, M. D. F. V. Souza, S. F. Cortes, and V. S. Lemos, “Mechanism involved in the spasmolytic effect of a mixture of two triterpenes, cycloartenol and cycloeucalenol, isolated from Herissanthia tiubae in the guinea-pig ileum,” Planta Medica, vol. 71, no. 11, pp. 1025–1029, 2005. View at: Publisher Site | Google Scholar
  75. F. Palacios-Espinosa, M. Déciga-Campos, and R. Mata, “Antinociceptive, hypoglycemic and spasmolytic effects of Brickellia veronicifolia,” Journal of Ethnopharmacology, vol. 118, no. 3, pp. 448–454, 2008. View at: Publisher Site | Google Scholar
  76. O. Estrada, J. M. González-Guzmán, M. Salazar-Bookaman, A. Z. Fernández, A. Cardozo, and C. Alvarado-Castillo, “Pomolic acid of Licania pittieri elicits endothelium-dependent relaxation in rat aortic rings,” Phytomedicine, vol. 18, no. 6, pp. 464–469, 2011. View at: Publisher Site | Google Scholar
  77. M. E. González-Trujano, R. Ventura-Martínez, M. Chávez, I. Díaz-Reval, and F. Pellicer, “Spasmolytic and antinociceptive activities of ursolic acid and acacetin identified in Agastache mexicana,” Planta Medica, vol. 78, no. 8, pp. 793–799, 2012. View at: Publisher Site | Google Scholar
  78. S. Begum, Farhat, I. Sultana, B. S. Siddiqui, F. Shaheen, and A. H. Gilani, “Spasmolytic constituents from Eucalyptus camaldulensis var. obtusa leaves,” Journal of Natural Products, vol. 63, no. 9, pp. 1265–1268, 2000. View at: Publisher Site | Google Scholar
  79. R. Aquino, S. Tortora, S. Fkih-Tetouani, and A. Capasso, “Saponins from the roots of Zygophyllum gaetulum and their effects on electrically-stimulated guinea-pig ileum,” Phytochemistry, vol. 56, no. 4, pp. 393–398, 2001. View at: Publisher Site | Google Scholar
  80. A. Trute, J. Gross, E. Mutschler, and A. Nahrstedt, “In vitro antispasmodic compounds of the dry extract obtained from Hedera helix,” Planta Medica, vol. 63, no. 2, pp. 125–129, 1997. View at: Publisher Site | Google Scholar
  81. N. Ali, “Brine shrimp cytotoxicity of crude methanol extract and antispasmodic activity of α-amyrin acetate from Tylophora hirsuta Wall,” BMC Complementary and Alternative Medicine, vol. 13, article 135, 2013. View at: Publisher Site | Google Scholar
  82. A.-U. Khan, A.-H. Gilani, and Najeeb-Ur-Rehman, “Pharmacological studies on Hypericum perforatum fractions and constituents,” Pharmaceutical Biology, vol. 49, no. 1, pp. 46–56, 2011. View at: Publisher Site | Google Scholar
  83. E. J. Oliveira, M. A. Romero, M. S. Silva, B. A. Silva, and I. A. Medeiros, “Intracellular calcium mobilization as a target for the spasmolytic action of scopoletin,” Planta Medica, vol. 67, no. 7, pp. 605–608, 2001. View at: Publisher Site | Google Scholar
  84. V. Lakshmi, S. Kapoor, K. Pandey, and G. K. Patnaik, “Spasmolytic activity of Toddalia asiatica var. floribunda,” Phytotherapy Research, vol. 16, no. 3, pp. 281-282, 2002. View at: Publisher Site | Google Scholar
  85. I. Pavlović, A. Krunić, D. Nikolić et al., “Chloroform extract of underground parts of ferula heuffelii: Secondary metabolites and spasmolytic activity,” Chemistry & Biodiversity, vol. 11, no. 9, pp. 1417–1427, 2014. View at: Publisher Site | Google Scholar
  86. H. Sadraei, Y. Shokoohinia, S. E. Sajjadi, and M. Mozafari, “Antispasmodic effects of Prangos ferulacea acetone extract and its main component osthole on ileum contraction,” Research in Pharmaceutical Sciences, vol. 8, no. 2, pp. 137–144, 2013. View at: Google Scholar
  87. G. K. Patnaik, K. K. Banaudha, K. A. Khan, A. Shoeb, and B. N. Dhawan, “Spasmolytic activity of angelicin: A coumarin from Heracleum thomsoni,” Planta Medica, vol. 53, no. 6, pp. 517–520, 1987. View at: Publisher Site | Google Scholar
  88. Y. Sato, T. Akao, J.-X. He et al., “Glycycoumarin from Glycyrrhizae Radix acts as a potent antispasmodic through inhibition of phosphodiesterase 3,” Journal of Ethnopharmacology, vol. 105, no. 3, pp. 409–414, 2006. View at: Publisher Site | Google Scholar
  89. H. Nagai, Y. Yamamoto, Y. Sato, T. Akao, and T. Tani, “Pharmaceutical evaluation of cultivated Glycyrrhiza uralensis roots in comparison of their antispasmodic activity and glycycoumarin contents with those of licorice,” Biological & Pharmaceutical Bulletin, vol. 29, no. 12, pp. 2442–2445, 2006. View at: Publisher Site | Google Scholar
  90. O. Desire, C. Rivière, R. Razafindrazaka et al., “Antispasmodic and antioxidant activities of fractions and bioactive constituent davidigenin isolated from Mascarenhasia arborescens,” Journal of Ethnopharmacology, vol. 130, no. 2, pp. 320–328, 2010. View at: Publisher Site | Google Scholar
  91. Y. Shi, D. Wu, Z. Sun et al., “Analgesic and uterine relaxant effects of isoliquiritigenin, a flavone from Glycyrrhiza glabra,” Phytotherapy Research, vol. 26, no. 9, pp. 1410–1417, 2012. View at: Publisher Site | Google Scholar
  92. Y. Sato, J.-X. He, H. Nagai, T. Tani, and T. Akao, “Isoliquiritigenin, one of the antispasmodic principles of Glycyrrhiza ularensis roots, acts in the lower part of intestine,” Biological & Pharmaceutical Bulletin, vol. 30, no. 1, pp. 145–149, 2007. View at: Publisher Site | Google Scholar
  93. H. Nagai, J.-X. He, T. Tani, and T. Akao, “Antispasmodic activity of licochalcone A, a species-specific ingredient of Glycyrrhiza inflata roots,” Journal of Pharmacy and Pharmacology, vol. 59, no. 10, pp. 1421–1426, 2007. View at: Publisher Site | Google Scholar
  94. A. Rojas, S. Cruz, H. Ponce-Monter, and R. Mata, “Smooth muscle relaxing compounds from Dodonaea viscosa,” Planta Medica, vol. 62, no. 2, pp. 154–159, 1996. View at: Publisher Site | Google Scholar
  95. L. Abu-Niaaj, M. Abu-Zarga, S. Sabri, and S. Abdalla, “Isolation and biological effects of 7-O-methyleriodictyol, a flavanone isolated from Artemisia monosperma, on rat isolated smooth muscles,” Planta Medica, vol. 59, no. 1, pp. 42–45, 1993. View at: Publisher Site | Google Scholar
  96. M. B. Da Rocha, F. V. M. Souza, C. D. S. Estevam, C. Pizza, A. E. G. Sant'Ana, and R. M. Marçal, “Antispasmodic effect of 4-methylepigallocatechin on guinea pig ileum,” Fitoterapia, vol. 83, no. 7, pp. 1286–1290, 2012. View at: Publisher Site | Google Scholar
  97. R. Lemmens-Gruber, E. Marchart, P. Rawnduzi, N. Engel, B. Benedek, and B. Kopp, “Investigation of the spasmolytic activity of the flavonoid fraction of Achillea millefolium s.l. on isolated guinea-pig ilea,” Arzneimittel-Forschung/Drug Research, vol. 56, no. 8, pp. 582–586, 2006. View at: Google Scholar
  98. S. Gorzalczany, V. Moscatelli, and G. Ferraro, “Artemisia copa aqueous extract as vasorelaxant and hypotensive agent,” Journal of Ethnopharmacology, vol. 148, no. 1, pp. 56–61, 2013. View at: Publisher Site | Google Scholar
  99. H. Fleer and E. J. Verspohl, “Antispasmodic activity of an extract from Plantago lanceolata L. and some isolated compounds,” Phytomedicine, vol. 14, no. 6, pp. 409–415, 2007. View at: Publisher Site | Google Scholar
  100. J. Engelbertz, M. Lechtenberg, L. Studt, A. Hensel, and E. J. Verspohl, “Bioassay-guided fractionation of a thymol-deprived hydrophilic thyme extract and its antispasmodic effect,” Journal of Ethnopharmacology, vol. 141, no. 3, pp. 848–853, 2012. View at: Publisher Site | Google Scholar
  101. M. I. Ragone, M. Sella, P. Conforti, M. G. Volonté, and A. E. Consolini, “The spasmolytic effect of Aloysia citriodora, Palau (South American cedrón) is partially due to its vitexin but not isovitexin on rat duodenums,” Journal of Ethnopharmacology, vol. 113, no. 2, pp. 258–266, 2007. View at: Publisher Site | Google Scholar
  102. A. H. Gilani, A.-U. Khan, M. N. Ghayur, S. F. Ali, and J. W. Herzig, “Antispasmodic effects of Rooibos tea (Aspalathus linearis) is mediated predominantly through K+-channel activation,” Basic & Clinical Pharmacology & Toxicology, vol. 99, no. 5, pp. 365–373, 2006. View at: Publisher Site | Google Scholar
  103. C. L. Macêdo, L. H. C. Vasconcelos, A. C. D. C. Correia et al., “Spasmolytic effect of galetin 3,6-dimethyl ether, a flavonoid obtained from Piptadenia stipulacea (Benth) Ducke,” Journal of Smooth Muscle Research, vol. 47, no. 5, pp. 123–134, 2011. View at: Publisher Site | Google Scholar
  104. F. Rodríguez-Ramos and A. Navarrete, “Solving the confusion of gnaphaliin structure: Gnaphaliin A and gnaphaliin B identified as active principles of Gnaphalium liebmannii with tracheal smooth muscle relaxant properties,” Journal of Natural Products, vol. 72, no. 6, pp. 1061–1064, 2009. View at: Publisher Site | Google Scholar
  105. X. Lozoya, M. Meckes, M. Abou-Zaid, J. Tortoriello, C. Nozzolillo, and J. T. Arnason, “Quercetin glycosides in Psidium guajava L. leaves and determination of a spasmolytic principle,” Archives of Medical Research, vol. 25, no. 1, pp. 11–15, 1994. View at: Google Scholar
  106. M. F. Melzig, H. H. Pertz, and L. Krenn, “Anti-inflammatory and spasmolytic activity of extracts from Droserae Herba,” Phytomedicine, vol. 8, no. 3, pp. 225–229, 2001. View at: Publisher Site | Google Scholar
  107. L. Krenn, G. Beyer, H. H. Pertz et al., “In vitro antispasmodic and anti-inflammatory effects of Drosera rotundifolia,” Arzneimittel-Forschung/Drug Research, vol. 54, no. 7, pp. 402–405, 2004. View at: Google Scholar
  108. W. C. Ko, H. L. Wang, C. B. Lei, C. H. Shih, M. I. Chung, and C. N. Lin, “Mechanisms of relaxant action of 3-O-methylquercetin in isolated guinea pig trachea,” Planta Medica, vol. 68, no. 1, pp. 30–35, 2002. View at: Publisher Site | Google Scholar
  109. O. Bergendorff and O. Sterner, “Spasmolytic flavonols from Artemisia abrotanum,” Planta Medica, vol. 61, no. 4, pp. 370-371, 1995. View at: Publisher Site | Google Scholar
  110. M. D. Herrera, E. Marhuenda, and A. Gibson, “Effects of genistein, an isoflavone isolated from Genista tridentata, on isolated guinea-pig ileum and guinea-pig ileal myenteric plexus,” Planta Medica, vol. 58, no. 4, pp. 314–316, 1992. View at: Publisher Site | Google Scholar
  111. F. Borrelli, N. Milic, V. Ascione et al., “Isolation of new rotenoids from Boerhaavia diffusa and evaluation of their effect on intestinal motility,” Planta Medica, vol. 71, no. 10, pp. 928–932, 2005. View at: Publisher Site | Google Scholar
  112. O. B. Balemba, T. D. Stark, S. Lösch et al., “(2R,3S,2''R,3''R)-manniflavanone, a new gastrointestinal smooth muscle L-type calcium channel inhibitor, which underlies the spasmolytic properties of Garcinia buchananii stem bark extract,” Journal of Smooth Muscle Research, vol. 50, no. 1, pp. 48–65, 2014. View at: Publisher Site | Google Scholar
  113. E. J. Verspohl, H. Fujii, K. Homma, and S. Buchwald-Werner, “Testing of Perilla frutescens extract and Vicenin 2 for their antispasmodic effect,” Phytomedicine, vol. 20, no. 5, pp. 427–431, 2013. View at: Publisher Site | Google Scholar
  114. N. F. De Moura, A. F. Morel, E. C. Dessoy et al., “Alkaloids, amides and antispasmodic activity of Zanthoxylum hyemale,” Planta Medica, vol. 68, no. 6, pp. 534–538, 2002. View at: Publisher Site | Google Scholar
  115. W.-J. He, T.-H. Fang, X. Ma, K. Zhang., Z.-Z. Ma, and P.-F. Tu, “Echinacoside elicits endothelium-dependent relaxation in rat aortic rings via an NO-cGMP pathway,” Planta Medica, vol. 75, no. 13, pp. 1400–1404, 2009. View at: Publisher Site | Google Scholar
  116. J. Yang, P. S. P. Ip, J. H. K. Yeung, and C.-T. Che, “Inhibitory effect of schisandrin on spontaneous contraction of isolated rat colon,” Phytomedicine, vol. 18, no. 11, pp. 998–1005, 2011. View at: Publisher Site | Google Scholar
  117. J.-M. Yang, P. S. P. Ip, C.-T. Che, and J. H. K. Yeung, “Relaxant effects of Schisandra chinensis and its major lignans on agonists-induced contraction in guinea pig ileum,” Phytomedicine, vol. 18, no. 13, pp. 1153–1160, 2011. View at: Publisher Site | Google Scholar
  118. Y. Hernández-Romero, J.-I. Rojas, R. Castillo, A. Rojas, and R. Mata, “Spasmolytic Effects, Mode of Action, and Structure-Activity Relationships of Stilbenoids from Nidema boothii,” Journal of Natural Products, vol. 67, no. 2, pp. 160–167, 2004. View at: Publisher Site | Google Scholar
  119. S. Estrada, A. Rojas, Y. Mathison, A. Israel, and R. Mata, “Nitric oxide/cGMP mediates the spasmolytic action of 3,4'-dihydroxy- 5,5'-dimethoxybibenzyl from Scaphyglottis livida,” Planta Medica, vol. 65, no. 2, pp. 109–114, 1999. View at: Publisher Site | Google Scholar
  120. S. Estrada, J. J. López-Guerrero, R. Villalobos-Molina, and R. Mata, “Spasmolytic stilbenoids from Maxillaria densa,” Fitoterapia, vol. 75, no. 7-8, pp. 690–695, 2004. View at: Publisher Site | Google Scholar
  121. C. Itthipanichpong, W. Kemsri, N. Ruangrungsi, and A. Sawasdipanich, “Antispasmodic effects of curcuminoids on isolated guinea-pig ileum and rat uterus,” Journal of the Medical Association of Thailand, vol. 86, no. 2, pp. S299–S309, 2003. View at: Google Scholar
  122. K. Seya, K.-I. Furukawa, S. Taniguchi et al., “Endothelium-dependent vasodilatory effect of vitisin C, a novel plant oligostilbene from Vitis plants (Vitaceae), in rabbit aorta,” Clinical Science, vol. 105, no. 1, pp. 73–79, 2003. View at: Publisher Site | Google Scholar
  123. M.-J. Liang, L.-C. He, and G.-D. Yang, “Screening, analysis and in vitro vasodilatation of effective components from Ligusticum Chuanxiong,” Life Sciences, vol. 78, no. 2, pp. 128–133, 2005. View at: Publisher Site | Google Scholar
  124. D. Rigano, C. Formisano, F. Senatore et al., “Intestinal antispasmodic effects of Helichrysum italicum (Roth) Don ssp. italicum and chemical identification of the active ingredients,” Journal of Ethnopharmacology, vol. 150, no. 3, pp. 901–906, 2013. View at: Publisher Site | Google Scholar
  125. S. Baldassano, L. Tesoriere, A. Rotundo, R. Serio, M. A. Livrea, and F. Mulè, “Inhibition of the mechanical activity of mouse ileum by cactus pear (Opuntia ficus Indica, L, Mill.) fruit extract and its pigment indicaxanthin,” Journal of Agricultural and Food Chemistry, vol. 58, no. 13, pp. 7565–7571, 2010. View at: Publisher Site | Google Scholar
  126. S. S. Gambhir, S. P. Sen, A. K. Sanyal, and P. K. Das, “Antispasmodic activity of the tertiary base of Daucus carota, Linn. seeds,” Indian Journal of Physiology and Pharmacology, vol. 23, no. 3, pp. 225–228, 1979. View at: Google Scholar
  127. M. Tsukiyama, T. Ueki, Y. Yasuda et al., “β2-adrenoceptor-mediated tracheal relaxation induced by higenamine from nandina domestica thunberg,” Planta Medica, vol. 75, no. 13, pp. 1393–1399, 2009. View at: Publisher Site | Google Scholar
  128. C.-H. Lin, F.-N. Ko, Y.-C. Wu, S.-T. Lu, and C.-M. Teng, “The relaxant actions on guinea-pig trachealis of atherosperminine isolated from Fissistigma glaucescens,” European Journal of Pharmacology, vol. 237, no. 1, pp. 109–116, 1993. View at: Publisher Site | Google Scholar
  129. F. Orallo, “Pharmacological effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in several rat isolated tissues,” Planta Medica, vol. 69, no. 2, pp. 135–142, 2003. View at: Publisher Site | Google Scholar
  130. A. M. El-Shafae and A. S. Soliman, “A pyranocoumarin and two alkaloids (one with antispasmodic effect) from Citrus deliciosa,” Die Pharmazie, vol. 53, no. 9, pp. 640–643, 1998. View at: Google Scholar
  131. C. Lin, C. Yang, F. Ko, Y. Wu, and C. Teng, “Antimuscarinic action of liriodenine, isolated from Fissistigma glaucescens, in canine tracheal smooth muscle,” British Journal of Pharmacology, vol. 113, no. 4, pp. 1464–1470, 1994. View at: Publisher Site | Google Scholar
  132. J. Yuan, J. Zhou, Z. Hu, G. Ji, J. Xie, and D. Wu, “The effects of jatrorrhizine on contractile responses of rat ileum,” European Journal of Pharmacology, vol. 663, no. 1-3, pp. 74–79, 2011. View at: Publisher Site | Google Scholar
  133. M. Zhao, Y. Xian, S. Ip, H. H. S. Fong, and C. Che, “A new and weakly antispasmodic protoberberine alkaloid from rhizoma coptidis,” Phytotherapy Research, vol. 24, no. 9, pp. 1414–1416, 2010. View at: Publisher Site | Google Scholar
  134. R. Sotníková, V. Kettmann, D. Kostálová, and E. Táborská, “Relaxant properties of some aporphine alkaloids from Mahonia aquifolium,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 19, no. 9, pp. 589–597, 1997. View at: Google Scholar
  135. K.-O. Hiller, M. Ghorbani, and H. Schlicher, “Antispasmodic and relaxant activity of chelidonine, protopine, coptisine, and Chelidonium majus extracts on isolated guinea-pig ileum,” Planta Medica, vol. 64, no. 8, pp. 758–760, 1998. View at: Publisher Site | Google Scholar
  136. L. Rastrelli, A. Capasso, C. Pizza, N. De Tommasi, and L. Sorrentino, “New protopine and benzyltetrahydroprotoberberine alkaloids from Aristolochia constricta and their activity on isolated guinea-pig ileum,” Journal of Natural Products, vol. 60, no. 11, pp. 1065–1069, 1997. View at: Publisher Site | Google Scholar
  137. R. C. Oliveira, J. T. Lima, L. A. A. Ribeiro et al., “Spasmolytic action of the methanol extract and isojuripidine from Solanum asterophorum Mart. (Solanaceae) leaves in guinea-pig ileum,” Zeitschrift fur Naturforschung - Section C Journal of Biosciences, vol. 61, no. 11-12, pp. 799–805, 2006. View at: Publisher Site | Google Scholar
  138. A.-U. H. Gilani, A. Khalid, Zaheer-ul-Haq, M. I. Choudhary, and Atta-ur-Rahman, “Presence of antispasmodic, antidiarrheal, antisecretory, calcium antagonist and acetylcholinesterase inhibitory steroidal alkaloids in Sarcococca saligna,” Planta Medica, vol. 71, no. 2, pp. 120–125, 2005. View at: Publisher Site | Google Scholar
  139. A. Khalid, Zaheer-Ul-Haq, M. N. Ghayur et al., “Cholinesterase inhibitory and spasmolytic potential of steroidal alkaloids,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 92, no. 5, pp. 477–484, 2004. View at: Publisher Site | Google Scholar
  140. Y. Zhang, Z. Long, Z. Guo et al., “Hydroxycinnamic acid amides from Scopolia tangutica inhibit the activity of M1 muscarinic acetylcholine receptor in vitro,” Fitoterapia, vol. 108, pp. 9–12, 2016. View at: Publisher Site | Google Scholar
  141. P. Pongkorpsakol, P. Wongkrasant, S. Kumpun, V. Chatsudthipong, and C. Muanprasat, “Inhibition of intestinal chloride secretion by piperine as a cellular basis for the anti-secretory effect of black peppers,” Pharmacological Research, vol. 100, pp. 271–280, 2015. View at: Publisher Site | Google Scholar
  142. R. Capasso, G. Aviello, B. Romano et al., “Modulation of mouse gastrointestinal motility by allyl isothiocyanate, a constituent of cruciferous vegetables (Brassicaceae): Evidence for TRPA1-independent effects,” British Journal of Pharmacology, vol. 165, no. 6, pp. 1966–1977, 2012. View at: Publisher Site | Google Scholar
  143. D. Kanjanapothi, P. Soparat, A. Panthong, P. Tuntiwachwuttikul, and V. Reutrakul, “A uterine relaxant compound from Zingiber cassumunar,” Planta Medica, vol. 53, no. 4, pp. 329–332, 1987. View at: Publisher Site | Google Scholar
  144. A. A. Moazedi, N. Dabir, M. K. Gharib Naseri, and M. R. Zadkarami, “The role of NO and cGMP in antispasmodic activity of Ruta chalepensis leaf extract on rat ileum,” Pakistan Journal of Biological Sciences, vol. 13, no. 2, pp. 83–87, 2010. View at: Publisher Site | Google Scholar
  145. H. Sadraei, M. Ghanadian, G. Asghari, E. Madadi, and N. Azali, “Antispasmodic and antidiarrhoeal activities of 6-(4-hydroxy-3- methoxyphenyl)-hexanonic acid from Pycnocycla spinosa Decne. exBoiss,” Research in Pharmaceutical Sciences, vol. 9, no. 4, pp. 279–286, 2014. View at: Google Scholar
  146. H. Sadraei, M. Ghanadian, G. Asghari, and N. Azali, “Antidiarrheal activities of isovanillin, iso-acetovanillon and Pycnocycla spinosa Decne ex.Boiss extract in mice,” Research in Pharmaceutical Sciences, vol. 9, no. 2, pp. 83–89, 2014. View at: Google Scholar
  147. R. C. Webb, “SMOOTH MUSCLE CONTRACTION AND RELAXATION,” Advances in Physiology Education, vol. 27, no. 4, pp. 201–206, 2003. View at: Publisher Site | Google Scholar
  148. “Copyright page,” Clinical Pharmacology & Therapeutics, vol. 73, no. 6, p. 578, 2003. View at: Publisher Site | Google Scholar
  149. O. Wintersteiner and J. D. Dutcher, “Curare alkaloids from Chondodendron tomentosum,” Science, vol. 97, no. 2525, pp. 467–470, 1943. View at: Publisher Site | Google Scholar
  150. H. H. Dale, W. Feldberg, and M. Vogt, “Release of acetylcholine at voluntary motor nerve endings,” The Journal of Physiology, vol. 86, no. 4, pp. 353–380, 1936. View at: Publisher Site | Google Scholar
  151. C. Galeffi, P. Scarpetti, and G. B. Marini-Bettolo, “Peinamine, a new bisbenzylisoquinoline alkaloid from arrow tips (pei-namô) of the Upper Orinoco.,” Il Farmaco; edizione scientifica, vol. 32, no. 9, pp. 665–671, 1977. View at: Google Scholar
  152. C. Galeffi, P. Scarpetti, and G. B. Marini Bettolo, “New curare alkaloids. II. New bisbenzylisoquinoline alkaloids from Abuta grisebachii (Menispermaceae),” Farmaco, Edizione Scientifica, vol. 32, no. 12, pp. 853–865, 1977. View at: Google Scholar
  153. Geiger and Hesse, “Darstellung des Atropins,” Annalen der Pharmacie, vol. 5, no. 1, pp. 43–81, 1833. View at: Publisher Site | Google Scholar
  154. J. F. Coulson and W. J. Griffin, “The alkaloids of Duboisia myoporoides. I. Aerial parts.,” Planta Medica, vol. 15, no. 4, pp. 459–466, 1967. View at: Publisher Site | Google Scholar
  155. J. F. Coulsen and W. J. Griffin, “The alkaloids of Duboisia myoporoides. II. Roots.,” Planta Medica, vol. 16, no. 2, pp. 174–181, 1968. View at: Publisher Site | Google Scholar
  156. E. Miraldi, A. Masti, S. Ferri, and I. Barni Comparini, “Distribution of hyoscyamine and scopolamine in Datura stramonium,” Fitoterapia, vol. 72, no. 6, pp. 644–648, 2001. View at: Publisher Site | Google Scholar
  157. J. Wisniak, “Pierre-Jean Robiquet,” Educación Química, vol. 24, pp. 139–149, 2013. View at: Publisher Site | Google Scholar
  158. A. N. Hayes and S. G. Gilbert, “Historical milestones and discoveries that shaped the toxicology sciences.,” EXS, vol. 99, pp. 1–35, 2009. View at: Publisher Site | Google Scholar
  159. G. Grynkiewicz and M. Gadzikowska, “Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs,” Pharmacological Reports, vol. 60, no. 4, pp. 439–463, 2008. View at: Google Scholar
  160. H. Keberle, J. W. Faigle, and M. Wilhelm, Beta-(para-halo-phenyl)-glutaric acid imides, https://patents.google.com/patent/US3634428A/en, 1972.
  161. F. A. Aboagye, G. H. Sam, G. Massiot, and C. Lavaud, “Julocrotine, a glutarimide alkaloid from Croton membranaceus,” Fitoterapia, vol. 71, no. 4, pp. 461-462, 2000. View at: Publisher Site | Google Scholar
  162. A. I. Suárez, Z. Blanco, F. Delle Monache, R. S. Compagnone, and F. Arvelo, “Three new glutarimide alkaloids from Croton cuneatus,” Natural Product Research (Formerly Natural Product Letters), vol. 18, no. 5, pp. 421–426, 2004. View at: Publisher Site | Google Scholar
  163. J. A. Oates, A. J. J. Wood, and N. J. Gross, “Ipratropium Bromide,” The New England Journal of Medicine, vol. 319, no. 8, pp. 486–494, 1988. View at: Publisher Site | Google Scholar
  164. R. Litta Modignani, M. Mazzolari, E. Barantani, D. Bertoli, and C. Vibelli, “Relative potency of the atropine-like effects of a new parasympatholytic drug, scopolamine-n-(Cyclopropy 1 methyl) bromide and those of hyoscine-n-butyl bromide,” Current Medical Research and Opinion, vol. 5, no. 4, pp. 333–340, 1977. View at: Publisher Site | Google Scholar
  165. P. K. Timms and R. B. Gibbons, “Latrodectism - Effects of the black widow spider bite,” Western Journal of Medicine, vol. 144, no. 3, pp. 315–317, 1986. View at: Google Scholar
  166. D. O. Toyama, A. C. Boschero, M. A. Martins, M. C. Fonteles, H. S. Monteiro, and M. H. Toyama, “Structure-function relationship of new crotamine isoform from the Crotalus durissus cascavella,” The Protein Journal, vol. 24, no. 1, pp. 9–19, 2005. View at: Publisher Site | Google Scholar
  167. F. N. McNamara, A. Randall, and M. J. Gunthorpe, “Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1),” British Journal of Pharmacology, vol. 144, no. 6, pp. 781–790, 2005. View at: Publisher Site | Google Scholar
  168. J. Gálvez, F. Sánchez De Medina, J. Jiménez, and A. Zarzuelo, “Effects of flavonoids on gastrointestinal disorders,” in Bioactive Natural Products (Part F), vol. 25 of Studies in Natural Products Chemistry, pp. 607–649, Elsevier, 2001. View at: Publisher Site | Google Scholar
  169. M. H. Mehmood, H. S. Siddiqi, and A. H. Gilani, “The antidiarrheal and spasmolytic activities of Phyllanthus emblica are mediated through dual blockade of muscarinic receptors and Ca2+ channels,” Journal of Ethnopharmacology, vol. 133, no. 2, pp. 856–865, 2011. View at: Publisher Site | Google Scholar
  170. V. Schlemper, A. Ribas, M. Nicolau, and V. Cechinel Filho, “Antispasmodic effects of hydroalcoholic extract of Marrubium vulgare on isolated tissues,” Phytomedicine, vol. 3, no. 2, pp. 211–216, 1996. View at: Publisher Site | Google Scholar
  171. Najeeb-ur-Rehman, S. Bashir, A. J. Al-Rehaily, and A.-H. Gilani, “Mechanisms underlying the antidiarrheal, antispasmodic and bronchodilator activities of Fumaria parviflora and involvement of tissue and species specificity,” Journal of Ethnopharmacology, vol. 144, no. 1, pp. 128–137, 2012. View at: Publisher Site | Google Scholar
  172. M. K. R. Peddireddy, “In vitro evaluation techniques for gastrointestinal motility,” Indian Journal of Pharmaceutical Education and Research (IJPER), vol. 45, no. 2, pp. 184–191, 2011. View at: Google Scholar
  173. A. Astudillo-Vázquez, R. Mata, and A. Navarrete, “El reino vegetal, fuente de agentes antiespasmódicos gastrointestinales y antidiarreicos,” Revista Latinoamericana de Química, vol. 37, pp. 7–44, 2009. View at: Google Scholar
  174. E. J. Ariens, P. A. Lehmann, and A. M. Simonis, Introduccion a la toxicologia general, MΘxico D.F, Diana, 1978.
  175. M. Khan, A.-U. Khan, Najeeb-Ur-Rehman, and A.-H. Gilani, “Gut and airways relaxant effects of Carum roxburghianum,” Journal of Ethnopharmacology, vol. 141, no. 3, pp. 938–946, 2012. View at: Publisher Site | Google Scholar
  176. F. J. Ehlert, “Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle,” Life Sciences, vol. 74, no. 2-3, pp. 355–366, 2003. View at: Publisher Site | Google Scholar
  177. J. G. Clement, “BaCl2-induced contractions in the guinea pig ileum longitudinal muscle: Role of presynaptic release of neurotransmitters and Ca2+ translocation in the postsynaptic membrane,” Canadian Journal of Physiology and Pharmacology, vol. 59, no. 6, pp. 541–547, 1981. View at: Publisher Site | Google Scholar
  178. A. M. Blackwood and T. B. Bolton, “Mechanism of carbachol‐evoked contractions of guinea‐pig ileal smooth muscle close to freezing point,” British Journal of Pharmacology, vol. 109, no. 4, pp. 1029–1037, 1993. View at: Publisher Site | Google Scholar
  179. S. Shore, C. G. Irvin, T. Shenkier, and J. G. Martin, “Mechanisms of histamine-induced contraction of canine airway smooth muscle,” Journal of Applied Physiology, vol. 55, no. 1, pp. 22–26, 1983. View at: Publisher Site | Google Scholar
  180. P. H. Ratz, K. M. Berg, N. H. Urban, and A. S. Miner, “Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus,” American Journal of Physiology-Cell Physiology, vol. 288, no. 4, pp. C769–C783, 2005. View at: Publisher Site | Google Scholar
  181. P. H. Ratz and S. F. Flaim, “Mechanism of 5-HT contraction in isolated bovine ventricular coronary arteries. Evidence for transient receptor-operated calcium influx channels,” Circulation Research, vol. 54, no. 2, pp. 135–143, 1984. View at: Publisher Site | Google Scholar
  182. M. J. Sumner, W. Feniuk, J. D. McCormick, and P. P. A. Humphrey, “Studies on the mechanism of 5‐HT1 receptor‐induced smooth muscle contraction in dog saphenous vein,” British Journal of Pharmacology, vol. 105, no. 3, pp. 603–608, 1992. View at: Publisher Site | Google Scholar
  183. B. N. Ames, W. E. Durston, E. Yamasaki, and F. D. Lee, “Carcinogens are mutagens: a simple test combining liver homogenates for activation and bacteria for detection,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 70, no. 8, pp. 2281–2285, 1973. View at: Publisher Site | Google Scholar
  184. D. M. Maron and B. N. Ames, “Revised methods for the Salmonella mutagenicity test,” Mutation Research, vol. 113, no. 3-4, pp. 173–215, 1983. View at: Publisher Site | Google Scholar
  185. H. Czeczot, B. Tudek, J. Kusztelak et al., “Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs,” Mutation Research - Genetic Toxicology and Environmental Mutagenesis, vol. 240, no. 3, pp. 209–216, 1990. View at: Publisher Site | Google Scholar
  186. M. Déciga-Campos, I. Rivero-Cruz, M. Arriaga-Alba et al., “Acute toxicity and mutagenic activity of Mexican plants used in traditional medicine,” Journal of Ethnopharmacology, vol. 110, no. 2, pp. 334–342, 2007. View at: Publisher Site | Google Scholar
  187. E. E. Elgorashi, S. F. Malan, G. I. Stafford, and J. van Staden, “Quantitative structure-activity relationship studies on acetylcholinesterase enzyme inhibitory effects of Amaryllidaceae alkaloids,” South African Journal of Botany, vol. 72, no. 2, pp. 224–231, 2006. View at: Publisher Site | Google Scholar
  188. R. Capasso, F. Borrelli, F. Capasso et al., “The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum,” Neurogastroenterology & Motility, vol. 18, no. 1, pp. 69–75, 2006. View at: Publisher Site | Google Scholar
  189. R. Capasso, F. Borrelli, M. G. Cascio et al., “Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB1 receptors,” British Journal of Pharmacology, vol. 155, no. 5, pp. 681–689, 2008. View at: Publisher Site | Google Scholar

Copyright © 2018 Edith Fabiola Martínez-Pérez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

2368 Views | 523 Downloads | 3 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.