通过交互 SAR 研究发现高活性和选择性的 D4 配体。

Discovery of highly potent and selective D4 ligands by interactive SAR study.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.

出版信息

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5077-81. doi: 10.1016/j.bmcl.2013.07.033. Epub 2013 Jul 23.

DOI:10.1016/j.bmcl.2013.07.033

PMID:23920439

Abstract

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with Ki 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with Ki (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands' arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.

摘要

一系列噻吩甲基苯基哌嗪被合成并测试了它们对五种多巴胺能受体亚型的亲和力。化合物 5f 对 D4 受体的选择性超过 1000 倍；类似物 5e 对 D4 受体的亲和力最高，Ki 为 3.9 nM。采用了一种交互式 SAR 方法，得到了 Ki（D4）低至 0.03 nM 的化合物 14a。分子对接研究表明，这是首次报道 D4 独特残基 Arg-186 与配体的芳烃部分之间存在芳基阳离子相互作用，这解释了在化合物结构的这个区域具有强负静电势的重要性。