Structural Requirements for Cannabinoid Receptor Probes 2232.5
Diarylpyrazoles
The most widely studied compound of the diarylpyrazole class is SR141716A (Ri-
monabant) ( 46 , Fig. 11) developed by Rinaldi-Carmona and co-workers at Sanofi
(Rinaldi-Carmona et al. 1994) and is currently undergoing clinical trials as an
antiobesity medication. This highly potent and selective CB 1 receptor ligand has
served as a unique pharmacological and biochemical tool for further character-
ization of the CB 1 cannabinoid receptor (Lan et al. 1999; Nakamura-Palacios et
al. 1999). In vitro, SR141716A antagonizes the inhibitory effects of cannabinoid
agonists on both mouse vas deferens (MVD) contractions and adenylyl cyclase
activity in rat brain membranes. SR141716A also antagonizes the pharmacological
and behavioral effects produced by CB 1 agonists after intraperitoneal (i.p.) or oral
administration (Rinaldi-Carmona et al. 1994).
Other diarylpyrazole ligands that have contributed to our understanding of CB 1
pharmacology are AM251 and AM281 (Lan et al. 1999), both of which are CB 1
antagonist/inverse agonists ( 47 and 48 respectively, Fig. 11) capable of displacing
[^3 H]SR141716A and [^3 H]CP-55,940 in CB 1 receptor membrane preparations. Both
AM251 and AM281 share the ability of SR141716A to attenuate the responses to
Fig. 11.Representative diarylpyrazole ligands