title: AT-1001: a high-affinity α3β4 nAChR ligand with novel nicotine-suppressive pharmacology.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline.
  
  
  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
  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.
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wu
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Gaiolini
authors.forename: Daniela
authors.initials: D
authors.lastname: Mercatelli
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schoch
authors.forename: Michelle
authors.initials: M
authors.lastname: Gorman
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramirez
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.forename: Taline V
authors.initials: TV
authors.lastname: Khroyan
authors.forename: Dennis
authors.initials: D
authors.lastname: Yasuda
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: Conrado
authors.initials: C
authors.lastname: Pascual
authors.forename: Xinmin Simon
authors.initials: XS
authors.lastname: Xie
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
mesh_terms: D000818:Animals; D002460:Cell Line; D058999:Drug-Seeking Behavior / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D000068580:Varenicline / Q000494:pharmacology
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D009842:Oligopeptides; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; D000431:Ethanol; D009538:Nicotine; C525167:larazotide acetate; D000068580:Varenicline