Two aromatic amino acids, Tyr<sup  >1</sup> and Phe<sup  >3</sup> or Phe<sup  >4</sup>, are important structural elements in opioid peptides because they interact with opioid receptors. The usefulness of an artificial amino acid residue <svg style="vertical-align:-0.0pt;width:12.2875px;" id="M3" height="12.7625" version="1.1" viewBox="0 0 12.2875 12.7625" width="12.2875"  xmlns="http://www.w3.org/2000/svg">
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</svg>-dimethylphenylalanine (Dmp) was investigated as an aromatic amino acid surrogate for several opioid peptides, including enkephalin, dermorphin, deltorphin, endomorphin, dynorphin A, and nociceptin peptides. In most peptides, substitutions of Phe<sup  >3</sup> by a Dmp residue produced analogs with improved receptor-binding affinity and selectivity, while the same substitution of Phe<sup  >4</sup> induced markedly reduced receptor affinity and selectivity. Interestingly, replacement of Tyr<sup  >1</sup> by Dmp produced analogs with unexpectedly high affinity or produced only a slight drop in receptor affinity and bioactivity for most peptides. Thus, Dmp is also a useful surrogate for the N-terminal Tyr residue in opioid peptides despite the lack of a phenolic hydroxyl group, which is considered necessary for opioid activity. The Dmp<sup  >1</sup>-substituted analogs are superior to <svg style="vertical-align:-0.0pt;width:12.2875px;" id="M5" height="12.7625" version="1.1" viewBox="0 0 12.2875 12.7625" width="12.2875"  xmlns="http://www.w3.org/2000/svg">
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</svg>-dimethyltyrosine (Dmt)<sup  >1</sup>-substituted analogs for high receptor selectivity since the latter generally have poor receptor selectivity. Thus, Dmp is very useful as an aromatic amino acid surrogate in opioid peptides and may be useful for developing other novel peptide mimetics with high receptor specificity.

Yusuke Sasaki

Akihiro Ambo

<svg style="vertical-align:-0.0pt" height="17.7125" version="1.1" viewBox="0 0 12.4375 17.7125" width="12.4375" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,17.65)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" /></g><g transform="matrix(.012,-0,0,-.012,8.225,9.488)"><path id="x2032" d="M227 744l-123 -338l-31 15l73 368q12 3 41.5 -8t36.5 -20z" /></g></svg>,<svg style="vertical-align:-0.16379pt" height="17.9125" version="1.1" viewBox="0 0 12.4375 17.9125" width="12.4375" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,17.65)"><path id="x36" d="M137 343l67 33q37 17 63 17q79 0 129.5 -53t50.5 -131q0 -92 -58 -156.5t-147 -64.5t-147 68t-58 182q0 63 17 119t43 95.5t61.5 72t69 52t67.5 31.5q62 22 128 33l6 -32q-56 -11 -108 -35q-149 -71 -184 -231zM227 337q-47 0 -95 -27q-6 -23 -6 -70q0 -93 36 -155.5&#xA;t96 -62.5q53 0 78 45.5t25 105.5q0 68 -35 116t-99 48z" /></g><g transform="matrix(.012,-0,0,-.012,8.225,9.488)"><use xlink:href="#x2032"/></g></svg>-Dimethylphenylalanine: A Useful Aromatic Amino Acid Surrogate for Tyr or Phe Residue in Opioid Peptides

Pharmaceutical compounds represent a rapidly emerging class of environmental contaminants. Such compounds were recently classified by the U.S. Geological Survey, including several antibiotics. An LC-MS/MS screening method for the top five antibiotics in drinking water was developed and validated using a Shimadzu LC-MS-IT-TOF. The separation was performed using a Waters Acquity UPLC BEH C18 column with a gradient elution. Sulfamethazine was exposed to conditions intended to mimic drinking water chlorination, and samples were collected and quenched with excess sodium sulfite. Kinetics of sulfamethazine degradation was followed as well as the formation of the major chlorinated byproduct (<svg style="vertical-align:-0.17555pt;width:23.362499px;" id="M2" height="10.9125" version="1.1" viewBox="0 0 23.362499 10.9125" width="23.362499"  xmlns="http://www.w3.org/2000/svg">
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</svg> 313). For the screening method, all five antibiotic peaks were baseline resolved within 5 minutes. Additionally, precision and accuracy of the screening method were less than 15&#x25;. Degradation of sulfamethazine upon exposure to drinking water chlorination occurred by first order kinetics with a half-life of <svg style="vertical-align:-0.3135pt;width:52.237499px;" id="M3" height="11.2625" version="1.1" viewBox="0 0 52.237499 11.2625" width="52.237499"  xmlns="http://www.w3.org/2000/svg">
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</svg><sup  >4</sup>&#x2009;min (approximately 37 days) with measurements starting 5 minutes after chlorination. Likewise, the formation of the major chlorinated product occurred by first order kinetics with a rate constant of <svg style="vertical-align:-0.3135pt;width:52.237499px;" id="M4" height="11.075" version="1.1" viewBox="0 0 52.237499 11.075" width="52.237499"  xmlns="http://www.w3.org/2000/svg">
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</svg><sup  >&#x2212;2</sup>. The proposed identification of the chlorinated product was 4-amino-(5-chloro-4,6-dimethyl-2-pyrimidinyl)-benzenesulfonamide (C<sub  >12</sub>H<sub  >13</sub>N<sub  >4</sub>O<sub  >2</sub>SCl) using <svg style="vertical-align:-0.17554pt;width:28.762501px;" id="M5" height="11.625" version="1.1" viewBox="0 0 28.762501 11.625" width="28.762501"  xmlns="http://www.w3.org/2000/svg">
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</svg> spectra and databases searches of SciFinder and ChemSpider.

Tyler C. Melton

Stacy D. Brown

The Fate of Sulfamethazine in Sodium-Hypochlorite-Treated Drinking Water: Monitoring by LC-<svg style="vertical-align:-0.20473pt" height="13.875" version="1.1" viewBox="0 0 29.924999 13.875" width="29.924999" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,13.55)"><path id="x4D" d="M861 0h-263v28q61 5 73 22t12 97l-4 408h-4l-244 -548h-20l-224 534h-2l-15 -285q-5 -98 -3 -166q1 -34 19.5 -45t72.5 -17v-28h-233v28q45 5 62.5 17t22.5 43q11 65 19 183l14 208q3 36 3.5 55t-2.5 37.5t-6.5 25t-16.5 13t-25.5 8t-39.5 4.5v28h164l228 -501l232 501&#xA;h170v-28q-68 -6 -81 -21.5t-11 -91.5l9 -362q2 -80 15 -97t78 -22v-28z" /></g><g transform="matrix(.017,-0,0,-.017,15.208,13.55)"><path id="x53" d="M409 504l-29 -5q-16 60 -44.5 96t-86.5 36q-54 0 -82.5 -32t-28.5 -77q0 -51 30.5 -82.5t96.5 -65.5l35.5 -18t33 -19.5t33.5 -23.5l27 -25.5t24.5 -32t13.5 -36.5t6 -45q0 -80 -62 -134.5t-160 -54.5q-47 0 -98 15q-22 7 -50 21q-8 23 -27 155l30 7q7 -27 18 -52&#xA;t30 -51.5t49 -42.5t67 -16q56 0 88 32.5t32 87.5q0 51 -31.5 82t-98.5 67q-80 44 -110 73q-55 53 -55 124q0 75 56 126.5t150 51.5q53 0 126 -23z" /></g><g transform="matrix(.012,-0,0,-.012,23.262,5.388)"><path id="x1D45B" d="M495 86q-46 -47 -87 -72.5t-63 -25.5q-43 0 -16 107l49 210q7 34 8 50.5t-3 21t-13 4.5q-35 0 -109.5 -72.5t-115.5 -140.5q-21 -75 -38 -159q-50 -10 -76 -21l-6 8l84 340q8 35 -4 35q-17 0 -67 -46l-15 26q44 44 85.5 70.5t64.5 26.5q35 0 10 -103l-24 -98h2&#xA;q42 56 97 103.5t96 71.5q46 26 74 26q9 0 16 -2.5t14 -11.5t9.5 -24.5t-1 -44t-13.5 -68.5q-30 -117 -47 -200q-4 -19 -3.5 -25t6.5 -6q21 0 70 48z" /></g></svg>-IT-TOF

A novel series of <i>N</i>-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.

Stéphane L. Raeppel

Frédéric Gaudette

Hannah Nguyen

Normand Beaulieu

James Wang

Christiane Maroun

Jeffrey M. Besterman

Arkadii Vaisburg

Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors

MDAN-21, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow><mml:mn>7</mml:mn></mml:mrow><mml:mrow><mml:mi>′</mml:mi></mml:mrow></mml:msup><mml:mtext>-</mml:mtext><mml:mo>{</mml:mo><mml:mn>2</mml:mn><mml:mtext>-</mml:mtext><mml:mo>[</mml:mo><mml:mo>(</mml:mo><mml:mn>7</mml:mn><mml:mtext>-</mml:mtext><mml:mo>{</mml:mo><mml:mn>2</mml:mn><mml:mtext>-</mml:mtext><mml:mo>[</mml:mo><mml:mo>(</mml:mo><mml:mo>{</mml:mo><mml:mo>(</mml:mo><mml:mn>5</mml:mn><mml:mi>α</mml:mi><mml:mo>,</mml:mo><mml:mn>6</mml:mn><mml:mi>α</mml:mi><mml:mo>)</mml:mo><mml:mtext>-</mml:mtext><mml:mn>4,5</mml:mn><mml:mtext>-Epoxy-</mml:mtext><mml:mn>3,14</mml:mn><mml:mtext>-dihydroxy-</mml:mtext><mml:mn>17</mml:mn><mml:mtext>-methylmorphin-</mml:mtext><mml:mn>6</mml:mn><mml:mtext>-yl</mml:mtext><mml:mo>}</mml:mo><mml:mtext>-aminocarbonyl</mml:mtext><mml:mo>)</mml:mo></mml:math><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mtext>metoxy</mml:mtext><mml:mo>]</mml:mo><mml:mtext>-</mml:mtext><mml:mtext>acetylamino</mml:mtext><mml:mo>}</mml:mo><mml:mtext>-heptylaminocarbonyl</mml:mtext><mml:mo>)</mml:mo><mml:mtext>-methoxy</mml:mtext><mml:mo>]</mml:mo><mml:mtext>-acetylamino</mml:mtext><mml:mo>}</mml:mo><mml:mtext>-naltrindole</mml:mtext></mml:math>, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (<i>Macaca mulatta</i>), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006–0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032–0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain.

Mario D. Aceto

Louis S. Harris

S. Stevens Negus

Matthew L. Banks

Larry D. Hughes

Eyup Akgün

Philip S. Portoghese

MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys

Oxazolidinone is a five-member heterocyclic ring exhibiting potential medicinal properties with preferential antibacterial activity. Scientists reported various synthetic procedures for this heterocyclic structure. Current review articles tried to cover each and every potential aspect of oxazolidinone like synthetic routes, pharmacological mechanism of action, medicinal properties, and current research activities.

Neha Pandit

Rajeev K. Singla

Birendra Shrivastava

Current Updates on Oxazolidinone and Its Significance

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International Journal of Medicinal Chemistry ceased publication in 2020 and is no longer accepting submissions.

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International Journal of Medicinal Chemistry

International Journal of Medicinal Chemistry publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis.

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International Journal of Medicinal Chemistry