TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

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 [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.

Green Apple e-Cigarette Flavorant Farnesene Triggers Reward-Related Behavior by Promoting High-Sensitivity nAChRs in the Ventral Tegmental Area

“…Additionally, we conducted locomotor assays to determine the effects of acute farnesene treatment on locomotor behavior in male and female mice. It is well understood that nicotine increases locomotor activity in mice ( Wall et al, 2017 ), and was recently determined that green apple flavorant, farnesol, also increased this behavior ( Avelar et al, 2019 ). Here, male and female mice were administered intraperitoneal injections of saline or 0.1 mg/kg farnesene, and locomotor activity was assessed in an open field test ( Fig.…”

Simulations of Promising Indolizidine—α6-β2 Nicotinic Acetylcholine Receptor Complexes

“…The development of new agents with affinities and potencies better than nicotine and other commercially available compounds is critical to further understanding nAChR involvement in the addiction process. We have seen further characterization of the “TC” compounds as high-affinity nAChR compounds [ 28 , 29 ]. Collectively, there is a lack of 6/ 2* subtype-selective agents that could be useful in treating addiction-related or neurodegenerative disorders.…”

Neurobiological Mechanisms of Nicotine Reward and Aversion

“…α 4* but not α 6* nAChRs regulate nicotine-induced bursting of VTA dopamine neurons ( Exley et al, 2011 ). The novel α 6 β 2* nAChR agonist TC299423 induced only modest rewarding effects in wild-type, which were enhanced in α 6 gain-of-function mutant mice ( Wall et al, 2017 ). However, TC299423 had no-effects, no-intravenous-nicotine self-administration in rats ( Wall et al, 2017 ).…”

“…The novel α 6 β 2* nAChR agonist TC299423 induced only modest rewarding effects in wild-type, which were enhanced in α 6 gain-of-function mutant mice ( Wall et al, 2017 ). However, TC299423 had no-effects, no-intravenous-nicotine self-administration in rats ( Wall et al, 2017 ). Using an intra-VTA self-administration procedure, it was shown that α 6 nAChR subunit knockout mice will self-administer similar quantities of nicotine in the VTA as wild-type mice, whereas α 4 subunit knockout mice self-administer far less nicotine ( Exley et al, 2011 ).…”