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TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

Wall, Teagan R. and Henderson, Brandon J. and Voren, George and Wageman, Charles R. and Deshpande, Purnima and Cohen, Bruce N. and Grady, Sharon R. and Marks, Michael J. and Yohannes, Daniel and Kenny, Paul J. and Bencherif, Merouane and Lester, Henry A. (2017) TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors. Frontiers in Pharmacology, 8 . Art. No. 641. ISSN 1663-9812. PMCID PMC5626944. https://resolver.caltech.edu/CaltechAUTHORS:20171013-114018950

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Abstract

(E)-5-(Pyrimidin-5-yl)-1,2,3,4,7,8-hexahydroazocine (TC299423) is a novel agonist for nicotinic acetylcholine receptors (nAChRs). We examined its efficacy, affinity, and potency for α6β2^∗ (α6β2-containing), α4β2^∗, and α3β4^∗ nAChRs, using [^(125)I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal ^(86)Rb^+ efflux, [^3H]-dopamine release, and [^3H]-acetylcholine release. TC299423 displayed an EC_(50) of 30–60 nM for α6β2^∗ nAChRs in patch-clamp recordings and [^3H]-dopamine release assays. Its potency for α6β2^∗ in these assays was 2.5-fold greater than that for α4β2^∗, and much greater than that for α3β4^∗-mediated [^3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9′S) nAChR mice, show that TC299423 elicits α6β2^∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9′S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4)β2^∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.3389/fphar.2017.00641DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5626944/PubMed CentralArticle
ORCID:
AuthorORCID
Henderson, Brandon J.0000-0003-0381-028X
Lester, Henry A.0000-0002-5470-5255
Additional Information:Copyright © 2017 Wall, Henderson, Voren, Wageman, Deshpande, Cohen, Grady, Marks, Yohannes, Kenny, Bencherif and Lester. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 25 June 2017. Accepted: 29 August 2017. Published: 26 September 2017. We thank Allan C. Collins, William A. Corrigall, John A. Lowe, and Paul Whiteaker for much advice during this research. Author Contributions: Experiments performed by TW, BH, GV, CW, PD, BC, SG, and MM. Analysis by TW, BH, GV, CW, BC, SG, MM, DY, MB, and HL. Research direction by MM, DY, PK, MB, and HL. Manuscript preparation and revision by TW, BH, BC, SG, MM, DY, PK, MB, and HL. Funding obtained by BH, MM, PK, MB, and HL. This work was supported by US National Institutes of Health grants DA015663 (MM and SG), DA019375 (HL, MM, and MB), DA033721 (BH), DA020686 (PK), and DA033622 (PK). Conflict of Interest Statement: When the research was conducted, MB and DY were employed by Targacept Inc. Targacept has since merged with Catalyst Biosciences. No entity or person now has any intellectual property, or commercial, or financial interest in TC299423. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funders:
Funding AgencyGrant Number
NIHDA015663
NIHDA019375
NIHDA033721
NIHDA020686
NIHDA033622
Subject Keywords:nicotine addiction, nicotinic acetylcholine receptors, neuroprotection, electrophysiology, transmitter release, a6b2^*, hexahydroazocine, pyrimidine
PubMed Central ID:PMC5626944
Record Number:CaltechAUTHORS:20171013-114018950
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171013-114018950
Official Citation:Wall TR, Henderson BJ, Voren G, Wageman CR, Deshpande P, Cohen BN, Grady SR, Marks MJ, Yohannes D, Kenny PJ, Bencherif M and Lester HA (2017) TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors. Front. Pharmacol. 8:641. doi: 10.3389/fphar.2017.00641
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:82344
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:17 Oct 2017 22:05
Last Modified:10 Apr 2020 18:46

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