Characterization of the pharmacology of imidazolidinedione derivatives at cannabinoid CB1 and CB2 receptors

Sophie J. Govaerts, Giulio G. Muccioli, Emmanuel Hermans and Didier M. Lambert


Abstract

The pharmacology of 3-(2-ethylmorpholino)-5,5′-di(p-bromophenyl)-imidazolidinedione (DML20), 3-(1-hydroxypropyl)-5,5′-di(p-bromophenyl)-imidazolidinedione (DML21) and 3-heptyl-5,5′-di(p-bromophenyl)-imidazolidinedione (DML23) was extended by studying affinity and GTP binding modulation on cannabinoid receptor subtypes (CB1 and CB2) from rat tissues and human cannabinoid receptors expressed in Chinese Hamster Ovary cells. Competitive binding studies indicated that DML20, DML21 and DML23 are selective ligands for cannabinoid CB1 receptors. In rat cerebellum homogenates, DML20, DML21 and DML23 were unable to influence [35S]GTPS binding but competitively inhibit HU 210-induced [35S]GTPS binding (pKB of 6.11±0.14, 6.25±0.06 and 5.74±0.09, respectively), indicating that they act as cannabinoid CB1 receptor neutral antagonists. However, in CHO cells homogenates expressing selectively either human cannabinoid CB1 or CB2 receptors, they behaved as inverse agonists decreasing the [35S]GTPS binding, with similar efficacy. In conclusion, these derivatives exhibit different activities (neutral antagonism and inverse agonism) in the different models of cannabinoid receptors studied.

Author Keywords: Cannabinoid receptor; [35S]GTPS; 3-Alkyl-(5,5′-diphenyl)imidazolidinedione; Neutral antagonism; Inverse agonism