Studies toward the discovery of the next generation of antidepressants.: 3.: Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines
Studies toward the discovery of the next generation of antidepressants.: 3.: Dual 5-HT1A and serotonin transporter affinity within a class of N-aryloxyethylindolylalkylamines
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DOI：
10.1021/jm0304010
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发表时间：
2004-07-15
影响因子：
7.3
通讯作者：
Andree, TH
中科院分区：
文献类型：
--
作者：
Mewshaw, RE;Zhou, DH;Andree, TH
本发明描述了具有双5-羟色胺转运体和5-HT1a亲和力的N-芳氧基乙基芳烃基胺(5)。这些化合物是我们先前报道的哌啶基衍生物的截短类似物(3)。研究发现，这些化合物对5-HT1A受体和5-羟色胺转运体具有更相似的亲和力和功能活性。尽管5-HT1a的拮抗作用在整个系列5中并不是始终如一的，但一些分子特征被发现是获得高和平衡活性的关键。5-HT1a和5-HT1a转运体的亲和力受芳环中杂原子的适当放置和连接吲哚部分的连接长度的影响。在芳环中引入卤素通常会降低固有活性，在某些情况下会导致完全的5-HT1A拮抗剂。化合物33和34是完全的5-HT1A拮抗剂，5-HT1A受体的K-I值约为30 nM，5-HT转运体的K-I值分别约为5和0.5 nM。不幸的是，与我们之前的系列(3)类似，本报告中的化合物对α(1)受体也有很高的亲和力。
N-Aryloxylethylindolealkylamines (5) having dual 5-HT transporter and 5-HT1A affinity are described. These compounds represent truncated analogues of our previously reported piperidinyl derivatives (3). Compounds in this investigation were found to have more similar affinities and functional activities for the 5-HT1A receptor and 5-HT transporter. Though 5-HT1A antagonism is not consistently observed throughout series 5, several molecular features were found to be essential to obtain high and balanced activities. The proper placement of a heteroatom in the aryl ring and the length of the linkage used to tether the indole moiety had significant influence on 5-HT1A and 5-HT transporter affinities. Introduction of a halogen into the aryl ring usually lowered intrinsic activity and in some cases led to full 5-HT1A antagonists. Compounds 33 and 34 were observed to be full 5-HT1A antagonists with K-i values of approximately 30 nM for the 5-HT1A receptor and K-i values of 5 and 0.5 nM for the 5-HT transporter, respectively. Unfortunately, similar to our previous series (3), compounds in this report also had high affinity for the alpha(1) receptor.