Ooms Frédéric, Wouters Johan, Oscari Olivier, Happaerts Thierry, Bouchard Géraldine, Carrupt Pierre-Alain, Testa Bernard, Lambert Didier M
Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland.
J Med Chem. 2002 Apr 25;45(9):1748-56. doi: 10.1021/jm010896y.
A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [(35)S]-GTP gamma S binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.
为了描绘出药效团，研究了一组对人大麻素CB(1)受体具有亲和力的29种3-烷基-5-芳基咪唑烷二酮（乙内酰脲）的亲脂性和构象性质。这些分子构成了一种用于大麻素受体识别的新模板，因为：(a)它们的结构不同于经典大麻素配体；(b)至少三种化合物（20、21和23）的作用机制为拮抗作用。实际上，在使用大鼠小脑匀浆的[(35)S]-GTPγS结合试验中，它们表现为拮抗剂，没有任何反向激动剂成分。使用一组选定的化合物，通过反相高效液相色谱法测量实验亲脂性，并通过碎片法（CLOGP）和基于分子亲脂性势的构象依赖性方法（CLIP）进行计算。这些方法揭示了两种模型，它们区分了非极性和极性乙内酰脲的结合模式，并且至少对于化合物20、21和23，可以解释这一新的大麻素配体家族的作用机制。
