Synthesis and evaluation of a conditionally-silent agonist for the ¦Á7 nicotinic acetylcholine receptor

详细信息    查看全文

• 作者：Kinga Chojnacka ; Roger L. Papke ; Nicole A. Horenstein
• 关键词：Silent-agonist ; Allosteric modulator ; Ion-channel ; Nicotinic receptor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 July, 2013
• 年：2013
• 卷：23
• 期：14
• 页码：4145-4149
• 全文大小：885 K

文摘

We introduce the term ¡®silent agonists¡¯ to describe ligands that can place the ¦Á7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5¡ä-phenylanabaseine) was synthesized and identified as a new silent agonist for the ¦Á7 nAChR; it binds to the receptor but does not activate ¦Á7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C-C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the ¦Á7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of ¦Á7 nAChR ligands may constitute a new alternative for the development of ¦Á7 nAChR therapeutics.