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Secondary Ammonium Agonists Make Dual Cation-π Interactions in α4β2 Nicotinic Receptors

Post, Michael R. and Tender, Gabrielle S. and Lester, Henry A. and Dougherty, Dennis A. (2017) Secondary Ammonium Agonists Make Dual Cation-π Interactions in α4β2 Nicotinic Receptors. eNeuro, 4 (2). Art. No. 0032-17. ISSN 2373-2822. PMCID PMC5458768. doi:10.1523/ENEURO.0032-17.2017.

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A cation-π interaction between the ammonium group of an agonist and a conserved tryptophan termed TrpB is a near universal feature of agonist binding to nicotinic acetylcholine receptors (nAChRs). TrpB is one of five residues that form the aromatic box of the agonist binding site, and for the prototype agonists ACh and nicotine, only TrpB makes a functional cation-π interaction. We report that, in addition to TrpB, a significant cation-π interaction is made to a second aromatic, TyrC2, by the agonists metanicotine, TC299423, varenicline, and nornicotine. A common structural feature of these agonists, and a distinction from ACh and nicotine, is a protonated secondary amine that provides the cation for the cation-π interaction. These results indicate a distinction in binding modes between agonists with subtly different structures that may provide guidance for the development of subtype-selective agonists of nAChRs.

Item Type:Article
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URLURL TypeDescription CentralArticle
Post, Michael R.0000-0002-3214-7619
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2017 by the Society for Neuroscience. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Received January 26, 2017; accepted March 2, 2017; First published March 17, 2017. This work was supported by HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (100000065, Grant NS34407); HHS | NIH | National Institute on Drug Abuse (NIDA) (Funding 100000026, Grand DA 019375); and by Beckman Institute at Caltech. M.R.P. was supported by the NIH/NRSA Training Grant 5 T32 GM07616. The authors declare no competing financial interests.
Funding AgencyGrant Number
NIHDA 019375
Caltech Beckman InstituteUNSPECIFIED
NIH Predoctoral Fellowship5 T32 GM07616
Subject Keywords:Parkinson's disease; Addiction; Ion channels; Nicotinic acetylcholine receptors; Electrophysiology; Non-canonical amino acids
Issue or Number:2
PubMed Central ID:PMC5458768
Record Number:CaltechAUTHORS:20170612-100040551
Persistent URL:
Official Citation:Secondary Ammonium Agonists Make Dual Cation-π Interactions in α4β2 Nicotinic Receptors Michael R. Post, Gabrielle S. Tender, Henry A. Lester,, Dennis A. Dougherty eNeuro 17 March 2017, 4 (2) ENEURO.0032-17.2017; DOI: 10.1523/ENEURO.0032-17.2017
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:78095
Deposited By: Tony Diaz
Deposited On:12 Jun 2017 20:35
Last Modified:15 Nov 2021 17:36

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