AT‐1001: a high‐affinity α3β4 nAChR ligand with novel nicotine‐suppressive pharmacology

Abstract

The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001

High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

“…We have previously shown that AT-1001 blocks nicotine self-administration [26] and nicotine-induced reinstatement in rats [29], at doses similar to those in this study, at which it showed a decrease in acquisition of cocaine CPP and blockade of cocaine-induced behavioral sensitization. Nicotine and cocaine addiction often occur as co-morbid addictions, and human clinical and epidemiological reports show that cocaine-dependent individuals exhibit higher rates of cigarette smoking [52, 53], while cigarette smoking can predispose adolescent individuals to other forms of drug abuse [54].…”

“…However, 18-MC is not very selective for the α3β4 nAChR [40], and it cannot be ruled out that other neurotransmitter systems contribute to the anti-addictive effects of 18-MC. In contrast, AT-1001 and AT-1012 have nanomolar affinity for the human and rat α3β4 nAChR, are >80-fold selectivity for the α3β4 nAChR compared to the α4β2 and α7 nAChR [26, 27, 29] and do not significantly bind to other non-nicotinic receptors [26]. We recently showed that AT-1001 has low efficacy partial agonist activity at the human α3β4 nAChR transfected into oocytes, showing approximately 30% of the efficacy of acetylcholine [28].…”

“…Two compounds from this series, AT-1001 and AT-1012 have single-digit nanomolar potency for the α3β4 nAChR, and 80–100-fold selectivity for the α3β4 versus the α4β2 nAChRs [26, 27]. Both compounds are low efficacy partial agonists at the α3β4 nAChR [28] but potently inhibit epibatidine-induced Ca +2 flux in HEK cells transfected with α3β4 nAChRs, with an IC 50 of approximately 30–60 nM [27, 29]. In vitro electrophysiology experiments with human α3β4 nAChR-transfected oocytes showed that AT-1001 blocks acetylcholine (ACh) response by rapid desensitization of the receptor at the same concentration at which it exhibits partial agonist response, thereby acting as a functional antagonist at the α3β4 nAChR [28].…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…Systemic administration of the α7* nAChR agonist ABT-107, and the α4β2*/α6β2* agonist ABT-089 attenuates the reinstatement of nicotine seeking indicating an important role for α7* nAChRs and α4-, α6-, and β2-containing nAChRs, respectively, in this behavioral response [101]. A more recent study found that systemic administration of the α3β4* nAChR ligand AT-1001 decreases nicotine priming-induced reinstatement of drug seeking [102]. This emerging literature expands our understanding of the role of nAChR subtypes in nicotine seeking and identifies potential new targets for novel smoking cessation pharmacotherapies.…”

“…As we have emphasized throughout this review, the identification of novel therapeutic targets can be strongly informed and guided by preclinical investigations in rodent models of nicotine addiction, including the reinstatement model of smoking relapse. Indeed, much of our understanding of the dopaminergic, glutamatergic, and cholinergic mechanisms underlying nicotine seeking and relapse behavior has been delineated from research in rodent models [67, 71, 87, 91, 92, 102]. Mechanistically, different neurotransmitter systems also interact to influence nicotine-seeking behavior and smoking relapse.…”