Binding of tetrahydrocarboline derivatives at human 5-HT5A receptors
Binding of tetrahydrocarboline derivatives at human 5-HT5A receptors
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DOI：
10.1021/jm030080s
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发表时间：
2003-08-28
影响因子：
7.3
通讯作者：
Glennon, RA
中科院分区：
文献类型：
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作者：
Khorana, N;Smith, C;Glennon, RA
在早期发现5-甲基- 5h -1,2,3,4-四氢吡啶[4,3-b]吲哚（5-甲基-1,2,3,4-四氢- γ -卡波林；1）与小鼠5-HT5A受体结合的基础上，进行了初步的结构亲和性研究。本研究使用人类5-HT5A受体扩展了这些结构亲和力研究，并检查了1的其他类似物。结果发现：(a)这些化合物的亲和性在物种间差异不大；(b)完整的1,2,3,4-四氢- γ -卡波林环体系似乎是最佳的，N-2-（3（取代苯氧基）丙基）片段具有高亲和性；(c)结构相关的1,2,3,4-四氢- β -卡波林也与5-HT5A受体结合；(d)所有被检测的衍生物也对5-HT2A受体具有亲和性。有证据表明，5-HT5A和5-HT2A受体的亲和性可能不会协同变化，并且随着进一步的研究，可能会开发出具有增强5-HT5A选择性的类似物。
On the basis of an earlier finding that 5-methyl-5H-1,2,3,4-tetrahydropyrido[4,3-b]indole (5-methyl-1,2,3,4-tetrahydro-gamma-carboline; 1) binds at murine 5-HT5A receptors, preliminary structure-affinity studies were conducted. The present investigation extends these structure-affinity studies using human 5-HT5A receptors and examined additional analogues of 1. It was found (a) that there is little interspecies difference for the affinities of these compounds, (b) that an intact 1,2,3,4-tetrahydro-gamma-carboline ring system seems optimal and an N-2-(3(substituted-phenoxy)propyl) moiety results in high affinity, (c) that structurally related 1,2,3,4-tetrahydro-beta-carbolines also bind at 5-HT5A receptors, and (d) that all examined derivatives also possess affinity for 5-HT2A receptors. Evidence is provided that 5-HT5A and 5-HT2A receptor affinities probably do not covary and that it might be possible, with continued investigation, to develop analogues with enhanced 5-HT5A selectivity.