Scaffold Ranking and Positional Scanning Utilized in the Discovery of nAChR-Selective Compounds Suitable for Optimization Studies

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• 作者：Jinhua Wu ; Yaohong Zhang ; Laura E. Maida ; Radleigh G. Santos ; Gregory S. Welmaker ; Travis M. LaVoi ; Adel Nefzi ; Yongping Yu ; Richard A. Houghten ; Lawrence Toll ; Marc A. Giulianotti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：56
• 期：24
• 页码：10103-10117
• 全文大小：878K
• ISSN：1520-4804

文摘

Nicotine binds to nicotinic acetylcholine receptors (nAChR), which can exist as many different subtypes. The 伪4尾2 nAChR is the most prevalent subtype in the brain and possesses the most evidence linking it to nicotine seeking behavior. Herein we report the use of mixture based combinatorial libraries for the rapid discovery of a series of 伪4尾2 nAChR selective compounds. Further chemistry optimization provided compound 301, which was characterized as a selective 伪4尾2 nAChR antagonist. This compound displayed no agonist activity but blocked nicotine-induced depolarization of HEK cells with an IC₅₀ of approximately 430 nM. 301 demonstrated nearly 500-fold selectivity for binding and 40-fold functional selectivity for 伪4尾2 over 伪3尾4 nAChR. In total over 5 million compounds were assessed through the use of just 170 samples in order to identify a series of structural analogues suitable for future optimization toward the goal of developing clinically relevant smoking cessation medications.