TY - JOUR T1 - 3-Substituted Pyrazole Analogs of the CB<sub>1</sub> Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice Via Non-CB<sub>1</sub>, Non-CB<sub>2</sub> Mechanism JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.187815 SP - jpet.111.187815 AU - Jenny L. Wiley AU - Dana E. Selley AU - Pinglang Wang AU - Rudresha Kottani AU - Srinivas Gadthula AU - Anu Mahadevan Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/11/15/jpet.111.187815.abstract N2 - The prototypic CB1 cannabinoid receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent) and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB1-selective compounds and to explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB1 selectivity, with many lacking affinity for the CB2 receptor. Affinity tended to be better when [3H]SR141716, rather than [3H]CP55,940, was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well-correlated with their CB1 binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ9-tetrahydrocannabinol in mice, that their agonist-like effects were not blocked by rimonabant, that they were active in vivo in CB1(-/-) mice, and that they failed to stimulate [35S]GTPγS binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB1-selective cannabinoids that produce agonist-like effects in mice through a non-CB1, non-CB2 mechanism. ER -