Deconstruction of the 伪4尾2 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator Desformylflustrabromine

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• 作者：Nadezhda German ; Jin-Sung Kim ; Atul Jain ; Malgorzata Dukat ; Anshul Pandya ; Yilong Ma ; Maegan Weltzin ; Marvin K. Schulte ; Richard A. Glennon
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7259-7267
• 全文大小：925K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of 伪4尾2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using two-electrode voltage clamp techniques. Although the intact structure of 1 was found to be optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for 伪4尾2 versus 伪7 nACh receptors. Pharmacophoric features for the allosteric modulation of 伪4尾2 nACh receptors by 1 were identified.