title: Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.
abstract: The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.
authors.affiliation: Department of Neuroscience Biology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. hans.rollema@pfizer.com
authors.forename: H
authors.initials: H
authors.lastname: Rollema
authors.forename: L K
authors.initials: LK
authors.lastname: Chambers
authors.forename: J W
authors.initials: JW
authors.lastname: Coe
authors.forename: J
authors.initials: J
authors.lastname: Glowa
authors.forename: R S
authors.initials: RS
authors.lastname: Hurst
authors.forename: L A
authors.initials: LA
authors.lastname: Lebel
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: R S
authors.initials: RS
authors.lastname: Mansbach
authors.forename: R J
authors.initials: RJ
authors.lastname: Mather
authors.forename: C C
authors.initials: CC
authors.lastname: Rovetti
authors.forename: S B
authors.initials: SB
authors.lastname: Sands
authors.forename: E
authors.initials: E
authors.lastname: Schaeffer
authors.forename: D W
authors.initials: DW
authors.lastname: Schulz
authors.forename: F D
authors.initials: FD
authors.lastname: Tingley
authors.forename: K E
authors.initials: KE
authors.lastname: Williams
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D016540:Smoking Cessation / Q000379:methods*; D014162:Transfection; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D009538:Nicotine; D004298:Dopamine; D000068580:Varenicline