%A Wall,Teagan R.
%A Henderson,Brandon J.
%A Voren,George
%A Wageman,Charles R.
%A Deshpande,Purnima
%A Cohen,Bruce N.
%A Grady,Sharon R.
%A Marks,Michael J.
%A Yohannes,Daniel
%A Kenny,Paul J.
%A Bencherif,Merouane
%A Lester,Henry A.
%D 2017
%J Frontiers in Pharmacology
%C
%F
%G English
%K nicotine addiction,Neuroprotection,Electrophysiology,transmitter release,alpha6beta*,hexahydroazocine,Pyrimidine,nicotinic acetylcholine receptors
%Q
%R 10.3389/fphar.2017.00641
%W
%L
%M
%P
%7
%8 2017-September-26
%9 Original Research
%+ Prof Henry A. Lester,Division of Biology and Biological Engineering, California Institute of Technology,United States,lester@caltech.edu
%#
%! A small molecule probe for α6* and α4* nAChRs
%*
%<
%T TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors
%U https://www.frontiersin.org/articles/10.3389/fphar.2017.00641
%V 8
%0 JOURNAL ARTICLE
%@ 1663-9812
%X (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 [125I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 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.