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

Background and PurposeThe 34 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 34 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. Experimental ApproachEffects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline. Key ResultsAT-1001 and its analogue AT-1012 were functionally selective as antagonists for 34 over 42 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at 34 nAChRs. In contrast, varenicline was a partial agonist at 42, a weak agonist at 34 and inhibited 42 at a much lower concentration than it inhibited 34 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm. Conclusions and ImplicationsThese findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.