Design, Synthesis, and Activity of a Series of Arylpyrid-3-ylmethanones as Type I Positive Allosteric Modulators of 伪7 Nicotinic Acetylcholine Receptors

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• 作者：Derk J. Hogenkamp ; Thomas A. Ford-Hutchinson ; Wen-Yen Li ; Edward R. Whittemore ; Ryan F. Yoshimura ; Minhtam B. Tran ; Timothy B. C. Johnstone ; Gavin D. Bascom ; Hannah Rollins ; Lena Lu ; Kelvin W. Gee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8352-8365
• 全文大小：504K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

A series of novel arylpyrid-3-ylmethanones (7a鈥?b>aa) were designed as modulators of 伪7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human 伪7 nAChRs expressed in Xenopus ooctyes. Structure鈥揳ctivity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC₅ response of 1200% and EC₅₀ = 0.18 渭M. Compound 7z was active in reversing the effect of scopolamine in the novel object recognition (NOR) paradigm with a minimum effective ip dose of 1.0 mg/kg (2.7 渭mol/kg). This effect was blocked by the selective 伪7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of 伪7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer鈥檚 disease.