Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor.

Abstract LH-21 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1 H -1,2,4-triazole) was previously reported as a neutral antagonist at the cannabinoid CB 1 receptor which, despite its reported poor ability to penetrate into the brain, suppressed food intake and body weight in rats by intraperitoneal administration. In the present study, we studied the mechanism of action of LH-21 by characterizing its in vitro pharmacological properties and in vivo efficacy. LH-21 inhibited the binding of [ 3 H]CP55940 to cloned human and rat CB 1 receptors with IC 50 values of 631 ± 98 nM, and 690 ± 41 nM, respectively, and acted as an inverse agonist in a cAMP functional assay using cultured cells expressing human, rat or mouse CB 1 receptor. The compound was shown to be brain-penetrant in rats by intravenous administration. Importantly, a single dose of LH-21 (60 mg/kg, i.p.) caused a similar suppression of overnight food intake and body weight gain in wild-type and CB 1 receptor knockout mice. Our results suggest that LH-21 is a low affinity inverse agonist for the CB 1 receptor and does not act on the CB 1 receptor to inhibit food intake in mice.