2-Substituted tryptamines:: Agents with selectivity for 5-HT6 serotonin receptors
2-Substituted tryptamines:: Agents with selectivity for 5-HT6 serotonin receptors
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DOI：
10.1021/jm990550b
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发表时间：
2000-03-09
影响因子：
7.3
通讯作者：
Lee, DKH
中科院分区：
文献类型：
--
作者：
Glennon, RA;Lee, M;Lee, DKH
设计并制备了几种2-烷基-5-甲氧基色胺类似物作为潜在的5-HT 6 - 5-羟色胺激动剂。发现5-HT 6受体在吲哚2-位容纳小的烷基取代基，并且所得化合物可以与血清素的亲和力相当的亲和力结合。特别是，2-乙基-5-甲氧基-N，N-二甲基色胺（8）与人5-HT 6受体（Ki = 16 nM）的结合亲和力高于5-HT（Ki = 75 nM），是一种完全激动剂，在激活腺苷酸环化酶方面至少与5-羟色胺（K-act = 5.0 nM）一样有效（8：K-act = 3.6 nM）。化合物8对几种其他5-HT受体群体显示出适度的亲和力，特别是h5-HT 1A（Ki = 170 nM）、h5-HT 1D（Ki = 290 nM）和h5-HT 7（Ki = 300 nM）受体，但在其他方面具有相当的选择性。化合物8代表迄今报道的第一个和最具选择性的6-HT 6激动剂。用苯基取代2-乙基取代基产生保留5-HT 6受体亲和力的化合物（即，10：Ki = 20 nM），但缺乏激动剂特征。2-取代色胺，然后，可能允许进入一个新的类别5-HT 6激动剂和拮抗剂。
Several 2-alkyl-5-methoxytryptamine analogues were designed and prepared as potential 5-HT6 serotonin agonists. It was found that 5-HT6 receptors accommodate small alkyl substituents at the indole 2-position and that the resulting compounds can bind with affinities comparable to that of serotonin. In particular, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (8) binds with high affinity at human 5-HT6 receptors (K-i = 16 nM) relative to 5-HT (K-i = 75 nM) and was a full agonist, at least as potent (8: K-act = 3.6 nM) as serotonin (K-act = 5.0 nM), in activating adenylate cyclase. Compound 8 displays modest affinity for several other populations of 5-HT receptors, notably h5-HT1A (K-i = 170 nM), h5-HT1D (K-i = 290 nM), and h5-HT7 (K-i = 300 nM) receptors, but is otherwise quite selective. Compound 8 represents the first and most selective 6-HT6 agonist reported to date. Replacing the 2-ethyl substituent with a phenyl group results in a compound that retains 5-HT6 receptor affinity (i.e., 10: K-i = 20 nM) but lacks agonist character. 2-Substituted tryptamines, then, might allow entry to a novel class of 5-HT6 agonists and antagonists.