Cannabinoid receptors synthesis

Sanofi-Synthelabo researchers discovered pyrazole 53 and analogs to have potent Cannabinoid receptor-1 (CB-1) antagonist/inverse agonist activity and have progressed 53 into development for treatment of obesity and alcohol dependence. The synthesis of 53 was accomplished by heating the diketone sodium salt 51 with the aryl hydrazine hydrochloride in acetic acid to provide the intermediate 52, which was further derivatized... 

Deutsch D, Chin SA. Enzymatic synthesis and degradation of ananadmide, a cannabinoid receptor agonist. Biochem Pharmacol 1993 46 791-796. 

Devane WA, Axelrod J. Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Proc Natl Acad Sci USA 1994 91 6698-6701. 

Mathews WB, Ravert HR, Musachio JL, Frank RA, Rinaldi-Carmona M, Barth F, Dannals RF. Synthesis of [1SF] SR144385 a selective radioligand for positron emission tomographic studies of brain cannabinoid receptors. J Labelled Compd Radiopharm 1994 42 589-596. 

F. R., Astruc-Diaz, F., Thompson, . M., Cavasotto, C. N., Naguib, M. (2009) 2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists design, synthesis, and binding mode prediction through ligand-steered modeling. ChemMedChem 4, 1615-1629. 

Pro-inflammatory cytokines (see p. 432 et seq.) can also induce sleep, the effect depending on the concentration of the cytokine and the time of day. The effect on the sleep profile (increased non-REM and decreased REM sleep) appears to depend on the increased synthesis of prostaglandin D2 and nitric oxide which then alter the circadian rhythm. It is also known that some pro-inflammatory cytokines can affect the reuptake of 5-HT which plays an important role in regulating the sleep-wake profile. The endogenous fatty acid, oleamide, can cause sedation and induce sleep by activating cannabinoid receptors but also by potentiating the action of benzodiazepines on their receptor sites. Whether such action is of physiological relevance is presently unknown. 

Endogenous ligands for the cannabinoid receptor have not yet been identified. Arachidonylethanolamide, a new arachidonic acid derivative named anandamide, was isolated from porcine brain. Its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. It inhibits the specific binding of a labelled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands, and produces a concentration-dependent inhibition of the electrically-evoked twitch response of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Similar compounds were synthesized and their pharmacological properties were investigated. 

Deutsch, D. G. and Chin, S. A., Enzymatic Synthesis and Degradation of Anandamide, A Cannabinoid Receptor Agonist, Biochemical Pharmacology, 46(5) 791-796 (1993). 

Kruszka, K.K., and Gross, R.W. The ATP- and CoA-independent synthesis of arachidonoylethanolamide. A novel mechanism underlying the synthesis of the endogenous ligand of the cannabinoid receptor. J Biol Chem 269(20) 14345-14348, 1994. 

Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K (1996) Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N-acylphosphatidylethanolamine pathway in testis involvement of Ca(24-)-dependent transacylase and phosphodiesterase activities. Biochem Biophys Res Commun 218 113-117... 

Ooms, F., Wouters, J., Oscari, O., Happaerts, T., Bouchard, G., Carrupt, R A., Testa, B., Lambert, D. M. Exploration of the pharmacophore of 3-alkyl-5-arylimidazoUdinediones as new CB(1) cannabinoid receptor ligands and potential antagonists synthesis, lipophihcity, affinity, and molecular modelUng. J. Med. Chem. 2002, 45(9), 1748-1756. 

Hillard CJ, Manna S, Greenberg MJ, Dicamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, Campbell WB (1999) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CBI). J Pharmacol Exp Ther 289 1427-1433... 

Mussinu J-M, Ruiu S, Mule AC, Pau A, Carai MAM, Loriga G, Murineddu G, Pinna GA (2003) Tricyclic pyrazoles. Part 1 synthesis and biological evaluation of novel 1,4-dihydroindeno[l,2-c]pyrazol-based ligands for CBI and CB2 cannabinoid receptors. Bioorg Med Chem 11 251-263... 

Ruiu S, Pinna GA, Marchese G, Mussinu J-M, Saba P, Tambaro S, Casti P, Vargiu R, Pani L (2003) Synthesis and characterization of NESS 0327 a novel putative antagonist of the CBI cannabinoid receptor. J Pharmacol Exp Ther 306 363-370... 

Suhara Y, Takayama H, Nakane S, Miyashita T, Waku K, Sugiura T (2000) Synthesis and biological activities of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolicaUy stable ether-linked analogues. Chem Pharm Bull (Tokyo) 48 903-907... 

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