AT-1001: a high-affinity ?3?4 nAChR ligand with novel nicotine-suppressive pharmacology.

ABSTRACT:

Background and purpose

The ?3?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 ?3?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 ?3?4 over ?4?2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at ?3?4 nAChRs. In contrast, varenicline was a partial agonist at ?4?2, a weak agonist at ?3?4 and inhibited ?4?2 at a much lower concentration than it inhibited ?3?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.

SUBMITTER: Cippitelli A 

PROVIDER: S-EPMC4376460 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature