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米那普明构象受限类似物的合成及生物活性：(1S, 2R)-1-苯基-2-[(R)-1-氨基-2-丙炔基]-N,N-二乙基环丙烷甲酰胺是一类新型的NMDA受体通道阻滞剂。

Synthesis and biological activity of conformationally restricted analogues of milnacipran: (1S, 2R)-1-phenyl-2-[(R)-1-amino-2-propynyl]-N,N- diethylcyclopropanecarboxamide is a novel class of NMDA receptor channel blocker.

作者信息

Shuto S, Ono S, Imoto H, Yoshii K, Matsuda A

机构信息

Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.

出版信息

J Med Chem. 1998 Aug 27;41(18):3507-14. doi: 10.1021/jm980238m.

DOI:10.1021/jm980238m
PMID:9719604
Abstract

Conformationally restricted analogues of (+/-)-(Z)-2-aminomethyl-1-phenyl-N,N-diethylcyclopropanecarboxamide++ + [milnacipran, (+/-)-1] were designed on the basis of its characteristic cyclopropane structure and were synthesized enantioselectively to develop efficient NMDA receptor antagonists. Among these analogues, (1S,2R)-1-phenyl-2-[(R)-1-amino-2-propynyl]-N, N-diethylcyclopropanecarboxamide (2d) had one of the most potent affinities for the receptor, with a Ki value of 0.29 microM. The blockade of NMDA receptor channels expressed by Xenopus oocytes by 2d was investigated in detail, and 2d was identified as a new class of open channel blocker against this receptor.

摘要

基于（±）-（Z）-2-氨甲基-1-苯基-N，N-二乙基环丙烷甲酰胺[米那普明，（±）-1]的特征性环丙烷结构设计了其构象受限类似物，并对其进行对映选择性合成以开发高效的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。在这些类似物中，（1S，2R）-1-苯基-2- [（R）-1-氨基-2-丙炔基]-N，N-二乙基环丙烷甲酰胺（2d）对该受体具有最强的亲和力之一，其抑制常数（Ki）值为0.29微摩尔。详细研究了2d对非洲爪蟾卵母细胞表达的NMDA受体通道的阻断作用，2d被确定为针对该受体的新型开放通道阻滞剂。

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