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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors.
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Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors.

机译：一系列双（苯基烷基）胺的结构活性关系：N-甲基-D-天冬氨酸受体的有效亚型选择性抑制剂。

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摘要

A series of bis(phenylalkyl)amines, structural analogues of ifenprodil and nylidrin, were synthesized and tested for antagonism of N-methyl-D-aspartate (NMDA) receptors. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The bis(phenylalkyl)amines were selective antagonists of NR1A/2B receptors. Assayed under steady-state conditions, the most potent of these, N-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentylamine hydrochloride (20), has an IC50 value of 8 nM and >1000-fold selectivity with respect to NR1A/2A and NR1A/2C receptors. The structure-activity relationship of the bis(phenylalkyl)amine series indicates that the piperidine ring and alkyl chain substitutions common to NR2B-selective antagonists such as ifenprodil, CP 101,606, and Ro 25-6981 are not necessary to generate potent and selective ligands. The primary determinants of potency are the phenolic OH group, acting as a hydrogen bond donor, the distance between the two rings, and an electrostatic interaction between the receptor and the basic nitrogen atom. This study provides a framework for designing structurally novel NR2B-selective antagonists which may be useful for treatment of a variety of neurological disorders.
机译：合成了一系列双（苯基烷基）胺，艾芬地尔和尼立德林的结构类似物，并测试了其对N-甲基-D-天冬氨酸（NMDA）受体的拮抗作用。通过在非洲爪蟾卵母细胞中电记录来测定效能和亚基选择性，该卵母细胞表达了克隆的大鼠NMDA受体亚基的三种二元组合：NR1A与NR2A，NR2B或NR2C组合表达。双（苯烷基）胺是NR1A / 2B受体的选择性拮抗剂。在稳态条件下测定，其中最有效的盐酸盐N- [2-（4-羟苯基）乙基] -5-苯基戊胺盐酸盐（20）的IC50值为8 nM，相对于NR1A / 2A和NR1A / 2C受体。双（苯基烷基）胺系列的结构活性关系表明，NR2B选择性拮抗剂（如艾芬地尔，CP 101,606和Ro 25-6981）共有的哌啶环和烷基链取代对于产生有效的和选择性的配体不是必需的。效能的主要决定因素是作为氢键供体的酚羟基，两个环之间的距离以及受体与碱性氮原子之间的静电相互作用。这项研究为设计结构新颖的NR2B选择性拮抗剂提供了框架，该拮抗剂可用于治疗多种神经系统疾病。

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