Cannabinoid-1 receptor inverse

SR144528 has greater inverse intrinsic activity than AM630. If this interpretation of the data is valid, it is of course an indication that just as the intrinsic activities of CBi and CB2 receptor agonists can vary from compound to compound, so too the (inverse) intrinsic activities of cannabinoid receptor inverse agonists will not be the same for all such ligands. 

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... 

Bouaboula, M., Perrachon, S., Milligan, L., Canatt, X., Rinaldi-Carmona, M., Portier, M., Barth, F., Calandra, B., Pecceu, F., Lupker, J., Maffrand, J.-P., Le Fur, G., and Casellas, P. (1997). A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor. J. Biol. Ckem. 272 22330-22339. 

Rinaldi-Carmona, M., Le Duigou, A, Oustric, D., Barth, F., Bouaboula, M., Carayon, P., Casellas, P., Le Fur, G. Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system, J. Pharmacol. Exp. Ther. 1998, 287, 1038-1047. 

Rimonabant is an inverse agonist for CBl cannabinoid receptors, which is approved in Europe for weight-loss therapy, but has significant side effects on the central nervous system. 

Keywords Cannabinoid receptors Cannabinoid receptor agonists and antagonists Abnormal-cannabidiol Cannabidiol Inverse agonism... 

This chapter describes the in vitro and in vivo bioassays that have been most widely used to characterize ligands for CBi and/or CB2 receptors and reviews the ability of compounds commonly used in cannabinoid research as experimental tools to activate or block these receptors. The likelihood that the most widely used cannabinoid receptor antagonists are inverse agonists rather than neutral antagonists is also discussed, as is evidence for the presence in mammalian tissues of non-CBi, non-CB2 pharmacological targets for cannabinoids. 

Table 3. K, values of cannabinoid receptor antagonists/inverse agonists for the in vitro displacement of pH]CP55940from CBr and CB2-specific binding sites...

Pan X, Ikeda SR, Lewis DL (1998) SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2-t currents by reversal of tonic CB 1 cannabinoid receptor activity. Mol Pharmacol 54 1064-1072... 

Pertwee RG (2001) Cannabinoid receptors and pain. Prog Neurobiol 63 569-611 Pertwee RG (2003) Inverse agonism at cannabinoid receptors. In IJzerman AP (ed) Inverse... 

Portier M, Rinaldi-Carmona M, Pecceu F, Combes T, Poinot-Chazel C, Calandra B, Barth F, Le Fur G, Casellas P (1999) SR 144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist. J Pharmacol Exp Ther 288 582-589... 

Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, Pertwee RG (1999a) Agonist-inverse agonist characterization at CB 1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. Br J Pharmacol 126 665-672... 

Ross RA, Gibson TM, Stevenson LA, Saha B, Crocker P, Razdan RK, Pertwee RG (1999b) Structural determinants of the partial agonist-inverse agonist properties of 6 -azidohex-2 -yne-A8-tetrahydrocannabinol at cannabinoid receptors. Br J Pharmacol 128 735-743... 

Bouaboula M, Desnoyer N, Carayon P, Combes T, CaseUas P (1999a) Gi protein modulation induced by a selective inverse agonist for the peripheral cannabinoid receptor CB2 impUcation for intraceUular signalization cross-regulation. Mol Pharmacol 55 473-480... 

Bouaboula M, Dussossoy D, CaseUas P (1999b) Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse agonist SR 144528. Implications for receptor biological responses. J Biol Chem 274 20397-20405... 

Researchers at Japan Tobacco (Osaka, Japan) reported the CB2 selective inverse agonist JTE-907, whose structure is characterized by the presence of a carboxamide group in the 3-position of a quinolone nucleus (66, Fig. 18) (Iwamura et al. 2001) with anti-inflammatory in vivo activity. Naphthyridine derivatives sharing some structural features of JTE-907 were recently reported as cannabinoid receptor ligands with a preference for the CB2 receptor (Ferrarini et al. 2004). 

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