Anzini M, Cappelli A, Vomero S, Seeber M, Menziani M C, Langer T, Hagen B, Manzoni C, Bourguignon J J
Dipartimento di Scienze Farmacobiologiche, Università degli Studi Magna Graecia di Catanzaro, Complesso Ninì Barbieri, 88021 Roccelletta di Borgia, Catanzaro, Italy.
J Med Chem. 2001 Apr 12;44(8):1134-50. doi: 10.1021/jm0009742.
The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910-2921) has been extended. A series of carboxamide derivatives endowed with differently substituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the carbonyl and aromatic moieties for interaction with the PBR binding site. The synthesis of most of these compounds involves Weinreb amidation of the appropriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PBR affinity similar to that shown by 1 and the presence of a basic N-ethyl-N-benzylaminomethyl group in 3-position of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational methods were used to furnish descriptors of the isolated ligands (indirect approaches) able to rationalize the variation in the binding affinity of the enlarged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributions to ligand-receptor interactions. Molecular descriptors which explicitly account for the electrostatic contribution to the interaction (CoMFA, CoMSIA, and surface approaches) perform well, but they do not improve the quantitative models. Moreover, useful hints for the identification of the antagonist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmacophoric approach. The ligand-receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestions for further experiments.
对与1-(2-氯苯基)-N-甲基-N-(1-甲基丙基)-3-异喹啉甲酰胺（PK11195，1）相关的外周苯二氮䓬受体（PBR）配体结合位点进行研究的合成-计算方法（Cappelli等人，《药物化学杂志》，1997年，40卷，2910 - 2921页）已得到扩展。设计了一系列具有不同取代平面芳族或杂芳族体系的羧酰胺衍生物，目的是获取关于羰基和芳族部分与PBR结合位点相互作用的拓扑要求的更多信息。这些化合物中大多数的合成涉及以适当内酯的Weinreb酰胺化作为关键步骤。在新合成的化合物中，最有效的化合物显示出与1相似的纳摩尔PBR亲和力，并且在喹啉核的3位存在碱性N-乙基-N-苄基氨基甲基基团。因此，它可被视为1的一类新型水溶性衍生物的首个实例。使用了几种计算方法来提供分离配体的描述符（间接方法），以合理化扩大的化合物系列结合亲和力的变化。通过大小和形状描述符（体积方法）获得了合理有效的QSAR模型，这些描述符编码了对配体-受体相互作用的短程贡献。明确考虑相互作用静电贡献的分子描述符（CoMFA、CoMSIA和表面方法）表现良好，但并未改进定量模型。此外，通过药效团方法得出的受体假设为受体三维建模中拮抗剂结合位点的识别提供了有用的线索（直接方法）。所获得的配体-受体复合物详细描述了相互作用的方式，并为进一步实验提供了有趣的建议。
