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Synthesis and evaluation of a conditionally-silent agonist for the ?7 nicotinic acetylcholine receptor.


ABSTRACT: We introduce the term 'silent agonists' to describe ligands that can place the ?7 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'-phenylanabaseine) was synthesized and identified as a new silent agonist for the ?7 nAChR; it binds to the receptor but does not activate ?7 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 ?7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of ?7 nAChR ligands may constitute a new alternative for the development of ?7 nAChR therapeutics.

SUBMITTER: Chojnacka K 

PROVIDER: S-EPMC3882203 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of a conditionally-silent agonist for the α7 nicotinic acetylcholine receptor.

Chojnacka Kinga K   Papke Roger L RL   Horenstein Nicole A NA  

Bioorganic & medicinal chemistry letters 20130523 14


We introduce the term 'silent agonists' to describe ligands that can place the α7 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'-phenylanabaseine) was synthesized and identified as a new silent agonist for the α7 nAChR; it binds to the receptor but does not activate α7 nAChR channel opening when applied alone,  ...[more]

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