AT-1001: a high-affinity [alpha]3[beta]4 nAChR ligand with novel nicotine-suppressive pharmacology

• Published in: British journal of pharmacology Vol. 172; no. 7; p. 1834
• Main Authors: Cippitelli, Andrea, Wu, Jinhua, Gaiolini, Kelly A, Mercatelli, Daniela, Schoch, Jennifer, Gorman, Michelle, Ramirez, Alejandra, Ciccocioppo, Roberto, Khroyan, Taline V, Yasuda, Dennis, Zaveri, Nurulain T, Pascual, Conrado, Xie, Xinmin (Simon), Toll, Lawrence
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.04.2015
• Subjects: Medical research; Nicotine; Rodents
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13034

Background and Purpose The [alpha]3[beta]4 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 [alpha]3[beta]4 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 Approach Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline. Key Results AT-1001 and its analogue AT-1012 were functionally selective as antagonists for [alpha]3[beta]4 over [alpha]4[beta]2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at [alpha]3[beta]4 nAChRs. In contrast, varenicline was a partial agonist at [alpha]4[beta]2, a weak agonist at [alpha]3[beta]4 and inhibited [alpha]4[beta]2 at a much lower concentration than it inhibited [alpha]3[beta]4 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 Implications These 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.