Cannabinoid-1 receptor inverse agonist

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. 

The papers listed in Table 3 and discussed in the preceding paragraph represent in vitro studies, and the question arises whether similar results are also obtained in vivo. This was examined in a series of studies on rats subjected to in vivo microdialysis the ligands under study were administered intraperitoneally or intravenously. Cannabinoids indeed decrease acetylcholine release in the dorsal hippocampus (Mishima et al. 2002). In the studies by Tzavara et al. (2001,2003a), in which cannabinoid agonists were not studied themselves, the CBi receptor inverse agonist SR 141716, which elicits effects opposite in direction to those of cannabi-... 

Shearman, L.P, Rosko, K.M., Fleischer, R., Wang, J., Xu, S., Tong, X.S. and Rocha, B.A. (2003) Antidepressant-like and anorectic effects of the cannabinoid CBj receptor inverse agonist AM251 in mice, Behav Pharmacol, 14 573-82. 

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. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

Cosenza M, Gifford AN, Gatley SJ, Pyatt B, Liu Q, Makriyannis A, Volkow ND. Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281. Synapse 2000 38 477-482. 

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...

---