Muccioli Giulio G, Martin Diana, Scriba Gerhard K E, Poppitz Wolfgang, Poupaert Jacques H, Wouters Johan, 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 Bruxelles, Belgium.
J Med Chem. 2005 Apr 7;48(7):2509-17. doi: 10.1021/jm049263k.
A set of 30 substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one (thiohydantoins) derivatives was synthesized, and their affinity for the human CB(1) cannabinoid receptor has been evaluated. These compounds are derived from the previously described cannabinoid ligands 5,5'-diphenylimidazolidine-2,4-dione (hydantoins). The replacement of the oxygen by a sulfur leads to an increase of the affinity while the function-i.e., inverse agonism-determined by [(35)S]GTPgammaS experiments remains unaffected. Finally, to evaluate the molecular parameters that could influence the affinity of the thiohydantoins, molecular electrostatic potential as well as lipophilicity calculations were undertaken on representative thiohydantoins and hydantoins derivatives. In conclusion, 5,5'-bis-(4-iodophenyl)-3-butyl-2-thioxoimidazolidin-4-one (31) and 3-allyl-5,5'-bis(4-bromophenyl)-2-thioxoimidazolidin-4-one (32) possess the highest affinity for the CB(1) cannabinoid receptor described to date for the hydantoin and thiohydantoins series when compared in a same bioassay.
合成了一组30种取代的5,5'-二苯基-2-硫代氧代咪唑烷-4-酮（硫代乙内酰脲）衍生物，并评估了它们对人CB(1)大麻素受体的亲和力。这些化合物衍生自先前描述的大麻素配体5,5'-二苯基咪唑烷-2,4-二酮（乙内酰脲）。用硫取代氧会导致亲和力增加，而通过[(35)S]GTPγS实验确定的功能（即反向激动作用）不受影响。最后，为了评估可能影响硫代乙内酰脲亲和力的分子参数，对代表性的硫代乙内酰脲和乙内酰脲衍生物进行了分子静电势以及亲脂性计算。总之，在相同生物测定中比较时，5,5'-双-(4-碘苯基)-3-丁基-2-硫代氧代咪唑烷-4-酮（31）和3-烯丙基-5,5'-双(4-溴苯基)-2-硫代氧代咪唑烷-4-酮（32）对CB(1)大麻素受体具有迄今为止乙内酰脲和硫代乙内酰脲系列中描述的最高亲和力。
