Conformationally constrained N₁-arylsulfonyltryptamine derivatives as 5-HT₆ receptor antagonists

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• 作者：Derek C. Cole ; William J. Lennox ; Joseph R. Stock ; John W. Ellingboe ; Hossein Mazandarani ; Deborah L. Smith ; Guoming Zhang ; Gregory J. Tawa and Lee E. Schechter
• 关键词：N₁-Arylsulfonyltryptamine ; 5-HT6 ; Serotonin ; Receptor ; Antagonist
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2005
• 出版时间：2005
• 年：2005
• 卷：15
• 期：21
• 页码：4780-4785
• 全文大小：164 K

文摘

Several series of conformationally constrained N₁-arylsulfonyltryptamine derivatives were prepared and tested for 5-HT₆ receptor binding affinity and ability to modulate cAMP production in a cyclase assay. The 3-piperidin-3-yl-, 3-(1-methylpyrrolidin-2-ylmethyl)-, and 3-pyrrolidin-3-yl-1H-indole arrays (8–13) appear to be able to adopt a conformation that allows high affinity 5-HT₆ receptor binding, while the β-carboline array 14 binds with a significantly weaker (10- to 100-fold) affinity. N₁-Benzenesulfonyl-3-piperidin-3-yl-1H-indole 9a is a high affinity full agonist with EC₅₀ = 24 nM. Several of the N₁-arylsulfonyl-3-(1-methylpyrrolidin-2-ylmethyl)-1H-indole derivatives behave as very potent antagonists ((S)-11r, (S)-11t; IC₅₀ = 0.8, 1.0 nM).