Binding of Sulfonyl-Containing Arylalkylamines at Human 5-HT6 Serotonin Receptors

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• 作者：Donald Sikazwe ; Mikhail L. Bondarev ; Ma//pubs.acs.org/images/entities/lstrok.gif" border="0">gorzata Dukat ; Jagadeesh B. Rangisetty ; Bryan L. Roth ; Richard A. Glennon
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 24, 2006
• 年：2006
• 卷：49
• 期：17
• 页码：5217 - 5225
• 全文大小：167K
• 年卷期：v.49,no.17(August 24, 2006)
• ISSN：1520-4804

文摘

Various sulfonyl-containing compounds (e.g. sulfonamides, sulfones) bind at human 5-HT₆ serotonin receptors,but it has been difficult relating the binding mode(s) of such agents to one another, even though manypossess a common SO₂ moiety, to identify a common pharmacophore model(s). On the basis of the hypothesisthat an ergoline-type conformation might be important for the binding of some sulfonamide-containingarylalkylamines, we prepared for examination at h5-HT₆ receptors a series of compounds, includingphenylethylamines 6, pyrroloethylamine 7, and phenylpiperazines 9. The results (with K_i values rangingfrom about 1 nM to >1000 nM) suggest that many of these agents likely bind in a related fashion, andstructure-affinity studies indicate that the benzenesulfonamide portion of the phenylethylamine andphenylpiperazine analogues can be "reversed", abbreviated to a sulfone, and moved to an adjacent positionwith relatively little impact on affinity. Although a benzenesulfonamide (or related arylsulfonamide) groupmight be common to various 5-HT₆ ligands, there appears to be some latitude with regard to the specificconstitution and location of the sulfonamide moiety even within the same arylalkylamine structural framework.A pharmacophore model is presented to account for some of the current findings.