Cannabinoids: A New Group of Agonists of PPARs

Sun, Yan; Bennett, Andy

doi:https://doi.org/10.1155/2007/23513

PPAR Research

On this page

Abstract References Copyright Related Articles

Review Article | Open Access

Volume 2007 | Article ID 023513 | https://doi.org/10.1155/2007/23513

Cannabinoids: A New Group of Agonists of PPARs

Yan Sun¹and Andy Bennett¹

Academic Editor: J. Vanden Heuvel

Received30 Apr 2007

Accepted13 Sept 2007

Published07 Nov 2007

Abstract

Cannabinoids have been used medicinally and recreationally for thousands of years and their effects were proposed to occur mainly via activation of the G-protein-coupled receptor CB1/CB2 (cannabinoid receptor 1/2). Discovery of potent synthetic analogs of the natural cannabinoids as clinically useful drugs is the sustained aim of cannabinoid research. This demands that these new compounds be free of the psychotropic effects that connected with the recreational use of cannabinoids. In preclinical studies cannabinoids displayed many of the characteristics of nonsteroidal anti-inflammatory drugs (NSAIDs) and it seems to be free of unwanted side effects. An increasing number of therapeutic actions of cannabinoid are being reported that do not appear to be mediated by either CB1 or CB2, and recently nuclear receptor superfamily PPARs (peroxisome-proliferator-activated receptors) have been suggested as the target of certain cannabinoids. This review summarizes the evidence for cannabinoid activation on PPARs and possible associated remedial potentials.

References

R. Mechoulam and Y. Gaoni, “Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids,” Tetrahedron, vol. 21, no. 5, pp. 1223–1229, 1965.
View at: Publisher Site | Google Scholar
A. C. Howlett, “Pharmacology of cannabinoid receptors,” Annual Review of Pharmacology Toxicology, vol. 35, pp. 607–634, 1995.
View at: Google Scholar
R. Mechoulam, E. Fride, and V. Di Marzo, “Endocannabinoids,” European Journal of Pharmacology, vol. 359, no. 1, pp. 1–18, 1998.
View at: Publisher Site | Google Scholar
S. A. Cook, J. A. Lowe, and B. R. Martin, “CB1 receptor antagonist precipitates withdrawal in mice exposed to $Δ$ 9- tetrahydrocannabinol,” Journal of Pharmacology and Experimental Therapeutics, vol. 285, no. 3, pp. 1150–1156, 1998.
View at: Google Scholar
T. Nadulski, F. Pragst, and G. Weinberg et al., “Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of thc verses standardized cannabis extract,” Therapeutic Drug Monitoring, vol. 27, no. 6, pp. 799–810, 2005.
View at: Publisher Site | Google Scholar
R. G. Pertwee, “Pharmacology of cannabinoid CB1 and CB2 receptors,” Pharmacology and Therapeutic, vol. 74, pp. 129–180, 1997.
View at: Google Scholar
B. R. Martin, D. R. Compton, and B. F. Thomas et al., “Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs,” Pharmacology Biochemistry and Behavior, vol. 40, no. 3, pp. 471–478, 1991.
View at: Publisher Site | Google Scholar
W. A. Devane, A. Breuer, T. Sheskin, T. U. C. Jarbe, M. S. Eisen, and R. Mechoulam, “A novel probe for the cannabinoid receptor,” Journal of Medicinal Chemistry, vol. 35, no. 11, pp. 2065–2069, 1992.
View at: Google Scholar
D. M. Lambert and C. J. Fowler, “The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications,” Journal of Medicinal Chemistry, vol. 48, no. 16, pp. 5059–5087, 2005.
View at: Publisher Site | Google Scholar
K.-O. Jonsson, S. Vandevoorde, D. M. Lambert, G. Tiger, and C. J. Fowler, “Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide,” British Journal of Pharmacology, vol. 133, no. 8, pp. 1263–1275, 2001.
View at: Google Scholar
A. C. Howlett, F. Barth, and T. I. Bonner et al., “International union of pharmacology. XXVII. Classification of cannabinoid receptors,” Pharmacological Reviews, vol. 54, no. 2, pp. 161–202, 2002.
View at: Publisher Site | Google Scholar
J. L. Wiley and B. R. Martin, “Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes,” Chemistry and Physics of Lipids, vol. 121, no. 1-2, pp. 57–63, 2002.
View at: Google Scholar
D. Smart and J. C. Jerman, “Anandamide: an endogenous activator of the vanilloid receptor,” Trends in Pharmacological Sciences, vol. 21, no. 4, p. 134, 2000.
View at: Publisher Site | Google Scholar
A. Calignano, R. G. La, and D. Piomelli, “Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide,” European Journal of Pharmacology, vol. 419, no. 2-3, pp. 191–198, 2001.
View at: Publisher Site | Google Scholar
V. Di Marzo, C. S. Breivogel, and Q. Tao et al., “Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain,” Neurochemical Research, vol. 75, no. 6, pp. 2434–2444, 2000.
View at: Google Scholar
C. S. Breivogel, G. Griffin, V. Di Marzo, B. R. Martin, R. K. Razdan, A. M. Zimmer, A. Zimmer, and B. R. Martin, “Evidence for a new G protein-coupled cannabinoid receptor in mouse brain,” Molecular Pharmacology, vol. 60, no. 1, pp. 155–163, 2001.
View at: Google Scholar
E. B. Russo, A. Burnett, B. Hall, and K. K. Parker, “Agonistic properties of cannabidiol at 5-HT1a receptors,” Neurochemical Research, vol. 30, no. 8, pp. 1037–1043, 2005.
View at: Publisher Site | Google Scholar
S. S. Davies, A. V. Pontsler, and G. K. Marathe et al., “Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor $γ$ ligands and agonists,” Journal of Biological Chemistry, vol. 276, no. 19, pp. 16015–16023, 2001.
View at: Publisher Site | Google Scholar
M. Gottlicher, E. Widmark, Q. Li, and J.-A. Gustafsson, “Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 10, pp. 4653–4657, 1992.
View at: Publisher Site | Google Scholar
K. Yu, W. Bayona, and C. B. Kallen et al., “Differential activation of peroxisome proliferator-activated receptors by eicosanoids,” Journal of Biological Chemistry, vol. 270, no. 41, pp. 23975–23983, 1995.
View at: Publisher Site | Google Scholar
M. V. Chakravarthy, Z. Pan, and Y. Zhu et al., ““New” hepatic fat activates PPAR $α$ to maintain glucose, lipid, and cholesterol homeostasis,” Cell Metabolism, vol. 1, no. 5, pp. 309–322, 2005.
View at: Publisher Site | Google Scholar
B. M. Forman, J. Chen, and R. M. Evans, “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors $α$ and $δ$ ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4312–4317, 1997.
View at: Publisher Site | Google Scholar
T. M. Willson, J. E. Cobb, and D. J. Cowan et al., “The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones,” Journal Medical Chemistry, vol. 39, pp. 665–668, 1996.
View at: Google Scholar
W. R. Oliver Jr., J. L. Shenk, and M. R. Snaith et al., “A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, pp. 5306–5311, 2001.
View at: Google Scholar
J. Fu, F. Oveisi, S. Gaetani, E. Lin, and D. Piomelli, “Oleoylethanolamide, an endogenous PPAR- $α$ agonist, lowers body weight and hyperlipidemia in obese rats,” Neuropharmacology, vol. 48, no. 8 SPEC. ISS., pp. 1147–1153, 2005.
View at: Publisher Site | Google Scholar
J. Fu, S. Gaetani, and F. Oveisi et al., “Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR- $α$ ,” Nature, vol. 425, no. 6953, pp. 90–93, 2003.
View at: Google Scholar
M. Guzmàn, V. J. Lo, J. Fu, F. Oveisi, C. Blàzquez, and D. Piomelli, “Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPAR- $α$ ),” Journal of Biological Chemistry, vol. 279, no. 27, pp. 27849–27854, 2004.
View at: Google Scholar
S. E. O'Sullivan, E. J. Tarling, A. J. Bennett, D. A. Kendall, and M. D. Randall, “Novel time-dependent vascular actions of Delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma,” Biochemical and Biophysical Research Communications, vol. 337, no. 3, pp. 824–831, 2005.
View at: Publisher Site | Google Scholar
R. B. Zurier, R. G. Rossetti, J. H. Lane, J. M. Goldberg, S. A. Hunter, and S. H. Burstein et al., “Dimethylheptyl-THC-11 OIC acid: a nonpsychoactive antiinflammatory agent with a cannabinoid template structure,” Arthritis and Rheumatism, vol. 41, no. 1, pp. 163–170, 1998.
View at: Publisher Site | Google Scholar
J. Liu, H. Li, S. H. Burstein, R. B. Zurier, and J. D. Chen, “Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid,” Molecular Pharmacology, vol. 63, pp. 983–992, 2003.
View at: Google Scholar
F. Maingret, A. J. Patel, M. Lazdunski, and E. Honorè, “The endocannabinoid anandamide is a direct and selective blocker of the background K $+$ channel TASK-1,” EMBO Journal, vol. 20, no. 1-2, pp. 47–54, 2001.
View at: Publisher Site | Google Scholar
V. Di Marzo, A. Fontana, and H. Cadas et al., “Formation and inactivation of endogenous cannabinoid anandanide in central neurons,” Nature, vol. 372, no. 6507, pp. 686–691, 1994.
View at: Google Scholar
C. J. Fowler, G. Tiger, A. Ligresti, M. L. Lòpez-Rodrìguez, and V. Di Marzo, “Selective inhibition of anandamide cellular uptake versus enzymatic hydrolysis—a difficult issue to handle,” European Journal of Pharmacology, vol. 492, no. 1, pp. 1–11, 2004.
View at: Publisher Site | Google Scholar
V. Di Marzo, T. Bisogno, P. L. De, D. Melck, and B. R. Martin, “Cannabimimetic fatty acid derivatives: The anandamide family and other endocannabinoids,” Current Medicinal Chemistry, vol. 6, no. 8, pp. 721–744, 1999.
View at: Google Scholar
S. H. Burstein, R. G. Rossetti, B. Yagen, and R. B. Zurier, “Oxidative metabolism of anandamide,” Prostaglandins and Other Lipid Mediators, vol. 61, no. 1-2, pp. 29–41, 2000.
View at: Publisher Site | Google Scholar
M. Bouaboula, S. Hilairet, J. Marchand, L. Fajas, G. Le Fur, and P. Casellas, “Anandamide induced PPAR $γ$ transcriptional activation and 3T3-L1 preadipocyte differentiation,” European Journal of Pharmacology, vol. 517, no. 3, pp. 174–181, 2005.
View at: Publisher Site | Google Scholar
Y. Sun, S. P. H. Alexander, D. A. Kendall, and A. J. Bennett, “Cannabinoids and PPAR $α$ signalling,” Biochemical Society Transactions, vol. 34, no. 6, pp. 1095–1097, 2006.
View at: Publisher Site | Google Scholar
V. J. Lo, J. Fu, and G. Astarita et al., “The nuclear receptor peroxisome proliferator-activated receptor- $α$ mediates the anti-inflammatory actions of palmitoylethanolamide,” Molecular Pharmacology, vol. 67, no. 1, pp. 15–19, 2005.
View at: Publisher Site | Google Scholar
C. E. Rockwell, N. T. Snider, J. T. Thompson, J. P. Vanden Heuvel, and N. E. Kaminski, “Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor $γ$ independently of cannabinoid receptors 1 and 2,” Molecular Pharmacology, vol. 70, no. 1, pp. 101–111, 2006.
View at: Publisher Site | Google Scholar
S. Vandevoorde and D. M. Lambert, “Focus on the three key enzymes hydrolysing endocannabinnoids as new drug targets,” Current Pharmaceutical Design, vol. 11, no. 20, pp. 2647–2668, 2005.
View at: Publisher Site | Google Scholar
N. Ueda, K. Yamanaka, and S. Yamamoto, “Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance,” Journal of Biological Chemistry, vol. 276, no. 38, pp. 35552–35557, 2001.
View at: Publisher Site | Google Scholar
J. Lengqvist, U. A. Mata De, and A.-C. Bergman et al., “Polyunsaturated fatty acids including docosahexaenoic and arachidonic acid bind to the retinoid X receptor $α$ ligand-binding domain,” Molecular and Cellular Proteomics, vol. 3, no. 7, pp. 692–703, 2004.
View at: Google Scholar
D. Rueda, I. Galve-Roperh, A. Haro, and M. Guzman, “The CB1 cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase,” Molecular Pharmacology, vol. 58, no. 4, pp. 814–820, 2000.
View at: Google Scholar
L. Gelman, L. Michalik, B. Desvergne, and W. Wahli, “Kinase signaling cascades that modulate peroxisome proliferator-activated receptors,” Current Opinion in Cell Biology, vol. 17, no. 2, pp. 216–222, 2005.
View at: Publisher Site | Google Scholar
R. G. Pertwee, “The pharmacology of cannabinoid receptors and their ligands: an overview,” International Journal of Obesity, vol. 30, suppl. 1, pp. S13–S18, 2006.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2007 Yan Sun and Andy Bennett. 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.

PDF Download Citation Order printed copies

Views

981

Downloads

1606

Citations