Format

Send to

Choose Destination
Br J Pharmacol. 2015 Apr;172(7):1834-45. doi: 10.1111/bph.13034. Epub 2015 Jan 23.

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

Author information

1
Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.

Abstract

BACKGROUND AND PURPOSE:

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.

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 α3β4 over α4β2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 nAChRs. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 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.

PMID:
25440006
PMCID:
PMC4376460
DOI:
10.1111/bph.13034
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center