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