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

We introduce the term 'silent agonists' to describe ligands that can place the alpha 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 alpha 7 nAChR; it binds to the receptor but does not activate alpha 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 alpha 7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of alpha 7 nAChR ligands may constitute a new alternative for the development of alpha 7 nAChR therapeutics. (C) 2013 Elsevier Ltd. All rights reserved.