Species comparison and pharmacological characterization of rat and human CB 2 cannabinoid receptors

Abstract

Pharmacological effects of cannabinoid ligands are thought to be mediated through cannabinoid CB 1 and CB 2 receptor subtypes. Sequence analysis revealed that rat and human cannabinoid CB 2 receptors are divergent and share 81% amino acid homology. Pharmacological analysis of the possible species differences between rat and human cannabinoid CB 2 receptors was performed using radioligand binding and functional assays. Pronounced species selectivity at the rat cannabinoid CB 2 receptor (50- to 140-fold) was observed with AM-1710 (3-(1,1-Dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo[c]chromen-6-one) and AM-1714 (3-(1,1-Dimethyl-heptyl)-1-9-dihydroxy-benzo[c]chromen-6-one). In contrast, JWH-015 ((2-Methyl-1-propyl-1H-indol-3-yl)-napthalen-1-yl-methanone) was 3- to 10-fold selective at the human cannabinoid CB 2 receptor. Endocannabinoid ligands were more human receptor selective. Cannabinoid CB 2 receptor antagonist, AM-630 ((6-Iodo-2-methyl-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl)-(4-methoxy-phenyl)-methanone) was more potent at the rat receptor in radioligand binding and functional assays than that of the human receptor. The findings of the pharmacological differences between the human and rat cannabinoid CB 2 receptors in this study provide critical information for characterizing cannabinoid ligands in in vivo rodent models for drug discovery purpose.