%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.