Muccioli Giulio G, Wouters Johan, Charlier Caroline, Scriba Gerhard K E, Pizza Teresa, Di Pace Pierluigi, De Martino Paolo, Poppitz Wolfgang, Poupaert Jacques H, Lambert Didier M
Unité de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, Avenue E. Mounier 73, UCL-CMFA 7340, B-1200 Brussels, Belgium.
J Med Chem. 2006 Feb 9;49(3):872-82. doi: 10.1021/jm050484f.
Obesity and metabolic syndrome, along with drug dependence (nicotine, alcohol, opiates), are two of the major therapeutic applications for CB(1) cannabinoid receptor antagonists and inverse agonists. In the present study, we report the synthesis and structure-affinity relationships of 1,5-diphenylimidazolidine-2,4-dione and 1,3,5-triphenylimidazolidine-2,4-dione derivatives. These new 1,3,5-triphenylimidazolidine-2,4-dione derivatives and their thio isosteres were obtained by an original pathway and exhibited interesting affinity and selectivity for the human CB(1) cannabinoid receptor. A [(35)S]-GTPgammaS binding assay revealed the inverse agonist properties of the compounds at the CB(1) cannabinoid receptor. Furthermore, molecular modeling studies were conducted in order to delineate the binding mode of this series of derivatives into the CB(1) cannabinoid receptor. 1,3-Bis(4-bromophenyl)-5-phenylimidazolidine-2,4-dione (25) and 1,3-bis(4-chlorophenyl)-5-phenylimidazolidine-2,4-dione (23) are the imidazolidine-2,4-dione derivatives possessing the highest affinity for the human CB(1) cannabinoid receptor reported to date.
肥胖症和代谢综合征，以及药物依赖（尼古丁、酒精、阿片类药物），是CB(1)大麻素受体拮抗剂和反向激动剂的两个主要治疗应用领域。在本研究中，我们报告了1,5 - 二苯基咪唑烷 - 2,4 - 二酮和1,3,5 - 三苯基咪唑烷 - 2,4 - 二酮衍生物的合成及其结构 - 亲和力关系。这些新型1,3,5 - 三苯基咪唑烷 - 2,4 - 二酮衍生物及其硫代类似物是通过一条原创途径获得的，并且对人CB(1)大麻素受体表现出有趣的亲和力和选择性。[(35)S]-GTPγS结合试验揭示了这些化合物在CB(1)大麻素受体上的反向激动剂特性。此外，还进行了分子模拟研究，以描绘这一系列衍生物与CB(1)大麻素受体的结合模式。1,3 - 双(4 - 溴苯基)-5 - 苯基咪唑烷 - 2,4 - 二酮（25）和1,3 - 双(4 - 氯苯基)-5 - 苯基咪唑烷 - 2,4 - 二酮（23）是迄今为止报道的对人CB(1)大麻素受体具有最高亲和力的咪唑烷 - 2,4 - 二酮衍生物。
