N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues.
N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues.
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DOI：
10.1021/cn500292d
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发表时间：
2015-07-15
影响因子：
5
通讯作者：
Fiedler WJ
中科院分区：
文献类型：
--
作者：
Nichols DE;Sassano MF;Halberstadt AL;Klein LM;Brandt SD;Elliott SP;Fiedler WJ
制备并研究了一系列 N-苄基化-5-甲氧基色胺类似物，特别强调了苄基间位的取代基。还包括几个 2,5-二甲氧基-4-碘苯乙胺 (2C-I) 的 N-苄基化类似物的平行系列，用于比较两种主要模板（即色胺和苯乙胺）。对血清素受体的广泛亲和力筛选表明，大多数化合物对 5-HT2 家族受体具有最高的亲和力。苄基对位的取代导致亲和力降低，而邻位或间位的取代则增强亲和力。一般来说，引入大的亲脂基团可以提高亲和力，而功能活性往往遵循相反的趋势。利用细胞内 Ca2+ 动员来测试化合物的功能活性。测量了人 5-HT2A、5-HT2B 和 5-HT2C 受体以及大鼠 5-HT2A 和 5-HT2C 受体的功能。亲和力和功能之间不存在一般相关性。几种色胺同系物的功能非常有效（EC50 值从 7.6 到 63 nM），但大多数是部分激动剂。小鼠头部抽搐试验表明，许多化合物会引起头部抽搐，并且这种行为与大鼠 5-HT2A 受体的功能效力之间存在显着相关性。
A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor.