3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB(1)) Receptor Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice via Non-CB(1), Non-CB(2) Mechanism

The prototypic cannabinoid type 1 (CB(1)) 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 structureactivity 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 CB(1)-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 CB(1) selectivity, with many lacking affinity for the CB(2) receptor. Affinity tended to be better when [(3)H]5-(4-chlorophenyl)-1(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1- yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [(3)H](-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydr oxy-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 CB(1) binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Delta(9)-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB(1) (-/-) mice, and they failed to stimulate guanosine-5'-O-(3-[(35)S] 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 CB(1)-selective cannabinoids that produce agonist-like effects in mice through a non-CB(1), non-CB(2) mechanism