Govaerts Sophie J, Muccioli Giulio G, Hermans Emmanuel, Lambert Didier M
Unité de Chimie pharmaceutique et de Radiopharmacie (73.40) Ecole de Pharmacie, Université Catholique de Louvain, 73, Avenue E. Mounier, UCL-CMFA 7340, B-1200 Bruxelles, Belgium.
Eur J Pharmacol. 2004 Jul 8;495(1):43-53. doi: 10.1016/j.ejphar.2004.05.023.
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]GTPgammaS binding but competitively inhibit HU 210-induced [35S]GTPgammaS 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]GTPgammaS binding, with similar efficacy. In conclusion, these derivatives exhibit different activities (neutral antagonism and inverse agonism) in the different models of cannabinoid receptors studied.
通过研究3-(2-乙基吗啉基)-5,5'-二(对溴苯基)-咪唑烷二酮(DML20)、3-(1-羟丙基)-5,5'-二(对溴苯基)-咪唑烷二酮(DML21)和3-庚基-5,5'-二(对溴苯基)-咪唑烷二酮(DML23)对大鼠组织大麻素受体亚型(CB1和CB2)以及中国仓鼠卵巢细胞中表达的人源大麻素受体的亲和力和GTP结合调节作用，扩展了它们的药理学研究。竞争性结合研究表明，DML20、DML21和DML23是大麻素CB1受体的选择性配体。在大鼠小脑匀浆中，DML20、DML21和DML23不能影响[35S]GTPγS结合，但能竞争性抑制HU 210诱导的[35S]GTPγS结合(其pKB分别为6.11±0.14、6.25±0.06和5.74±0.09)，表明它们作为大麻素CB1受体的中性拮抗剂发挥作用。然而，在选择性表达人源大麻素CB1或CB2受体的CHO细胞匀浆中，它们表现为反向激动剂，降低[35S]GTPγS结合，且效力相似。总之，这些衍生物在研究的不同大麻素受体模型中表现出不同的活性(中性拮抗和反向激动)。
