一种交互式 SAR 方法，用于发现新型噻吩探针作为 D2 样受体的配体，亲和力在亚纳摩尔范围内。

An interactive SAR approach to discover novel hybrid thieno probes as ligands for D2-like receptors with affinities in the subnanomolar range.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt, (phone: +202-27590716; fax: +202-27581041); Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität Jena, Philosophenweg 14, DE-07743 Jena.

出版信息

Chem Biodivers. 2013 Dec;10(12):2247-66. doi: 10.1002/cbdv.201300204.

DOI:10.1002/cbdv.201300204

PMID:24327445

Abstract

A series of [(phenylpiperazinyl)alkyl]-isoindole-1,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with Ki values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki (D4) value of 0.62 nM, and to its butyl analog, 10a, with Ki (D4) and Ki (D3) values of 0.03 and 0.26 nM, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4-subtype-receptor selectivity.

摘要

合成了一系列[(苯哌嗪基)烷基]-异吲哚-1,3-二酮衍生物，用作多巴胺受体探针。在这一系列中，化合物 6a 对 D4 和 D3 受体表现出最高的亲和力，Ki 值在纳摩尔范围内，D2/D4-和 D2/D3-选择性指数分别为 72 和 20。经过优化循环，得到了 D4 选择性配体噻吩-2-甲酰胺 9a，其 Ki（D4）值为 0.62 nM，以及其丁基类似物 10a，其 Ki（D4）和 Ki（D3）值分别为 0.03 和 0.26 nM。对接实验揭示了独特的 D4 残基 Arg186 在操纵配体的 D4-亚型受体选择性方面的重要性。