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Varenicline:  An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation

  • Jotham W. Coe*
    Jotham W. Coe
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
     Corresponding author. Phone:  +1-860-441-3271. Fax:  +1-860-686-0015. E-mail:  [email protected].
  • Paige R. Brooks
    Paige R. Brooks
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Michael G. Vetelino
    Michael G. Vetelino
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Michael C. Wirtz
    Michael C. Wirtz
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Eric P. Arnold
    Eric P. Arnold
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Jianhua Huang
    Jianhua Huang
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Steven B. Sands
    Steven B. Sands
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Thomas I. Davis
    Thomas I. Davis
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Lorraine A. Lebel
    Lorraine A. Lebel
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Carol B. Fox
    Carol B. Fox
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
    More by Carol B. Fox
  • Alka Shrikhande
    Alka Shrikhande
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • James H. Heym
    James H. Heym
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Eric Schaeffer
    Eric Schaeffer
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Hans Rollema
    Hans Rollema
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
    More by Hans Rollema
  • Yi Lu
    Yi Lu
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
    More by Yi Lu
  • Robert S. Mansbach
    Robert S. Mansbach
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Leslie K. Chambers
    Leslie K. Chambers
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • Charles C. Rovetti
    Charles C. Rovetti
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • David W. Schulz
    David W. Schulz
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • F. David Tingley
    F. David Tingley
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
  • , and 
  • Brian T. O'Neill
    Brian T. O'Neill
    Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340
Cite this: J. Med. Chem. 2005, 48, 10, 3474–3477
Publication Date (Web):April 23, 2005
https://doi.org/10.1021/jm050069n
Copyright © 2005 American Chemical Society

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    Supporting Info (2)»

    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 α4β2 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 α4β2 nAChR affinity and the desired in vivo dopaminergic profile.

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