title: Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
abstract: Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. jwcoe@pfizer.com
authors.forename: Jotham W
authors.initials: JW
authors.lastname: Coe
authors.forename: Paige R
authors.initials: PR
authors.lastname: Brooks
authors.forename: Michael G
authors.initials: MG
authors.lastname: Vetelino
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wirtz
authors.forename: Eric P
authors.initials: EP
authors.lastname: Arnold
authors.forename: Jianhua
authors.initials: J
authors.lastname: Huang
authors.forename: Steven B
authors.initials: SB
authors.lastname: Sands
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Davis
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Lebel
authors.forename: Carol B
authors.initials: CB
authors.lastname: Fox
authors.forename: Alka
authors.initials: A
authors.lastname: Shrikhande
authors.forename: James H
authors.initials: JH
authors.lastname: Heym
authors.forename: Eric
authors.initials: E
authors.lastname: Schaeffer
authors.forename: Hans
authors.initials: H
authors.lastname: Rollema
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mansbach
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Chambers
authors.forename: Charles C
authors.initials: CC
authors.lastname: Rovetti
authors.forename: David W
authors.initials: DW
authors.lastname: Schulz
authors.forename: F David
authors.initials: FD
authors.lastname: Tingley
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D016540:Smoking Cessation / Q000379:methods*; D000068580:Varenicline; D014982:Xenopus laevis
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000068580:Varenicline