Some inverse agonists of the cannabinoid CB1 receptor have been demonstrated to be anorectic antiobesity drug candidates. However, the first generation of CB1 inverse agonists, represented by rimonabant (SR141716A), otenabant and taranabant, are centrally active with a high level of psychiatric side effects. Hence, the discovery of CB1 inverse agonists with a chemical scaffold distinct from these holds promise for developing peripherally active CB1 inverse agonists with fewer side effects. We generated a new CB1 inverse agonist (4-(Bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229) from the class of benzhydryl piperazine analogs. This compound binds to CB1, more selectively than CB2, with a Ki value of 220 nM. Comparable CB1 binding was also observed by analogs 1-(Bis(4-fluorophenyl)methyl)-4-cinnamylpiperazine dihydrochloride (LDK1203) and 1-(Bis(4-fluorophenyl)methyl)-4-tosylpiperazine hydrochloride (LDK1222) which differed by the substitution on the piperazine ring where the piperazine of LDK1203 and LDK1222 are substituted by an alkyl group and by a tosyl group, respectively. LDK1229 exhibits efficacy comparable to SR141716A in antagonizing the basal G protein coupling activity of CB1 as indicated by a reduction in GTPγS binding. Consistent with inverse agonist behavior, increased cell surface localization of CB1 upon treatment with LDK1229 was also observed. Although docking and mutational analysis showed that LDK1229 forms similar interactions with the receptor as SR141716A, the benzhydryl piperazine scaffold is structurally distinct from the first generation CB1 inverse agonists; it offers new opportunities for developing novel CB1 inverse agonists through optimization of molecular properties such as the polar surface area and hydrophilicity, to reduce the central activity observed with SR141716A.
The American Society for Pharmacology and Experimental Therapeutics.