PT - JOURNAL ARTICLE AU - Wiley, Jenny L. AU - Selley, Dana E. AU - Wang, Pinglang AU - Kottani, Rudresha AU - Gadthula, Srinivas AU - Mahadeven, Anu TI - 3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB<sub>1</sub>) Receptor Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice via Non-CB<sub>1</sub>, Non-CB<sub>2</sub> Mechanism AID - 10.1124/jpet.111.187815 DP - 2012 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 433--444 VI - 340 IP - 2 4099 - http://jpet.aspetjournals.org/content/340/2/433.short 4100 - http://jpet.aspetjournals.org/content/340/2/433.full SO - J Pharmacol Exp Ther2012 Feb 01; 340 AB - The prototypic cannabinoid type 1 (CB1) 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 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]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [3H](−)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (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, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB1(−/−) mice, and they failed to stimulate guanosine-5′-O-(3-[35S]thio)-triphosphate 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.