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Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation

2005; American Chemical Society; Volume: 48; Issue: 10 Linguagem: Inglês

10.1021/jm050069n

1520-4804

Jotham W. Coe, Paige R. Brooks, Michael G. Vetelino, Michael Wirtz, Eric P. Arnold, Jianhua Huang, Steven B. Sands, Thomas I. Davis, Lorraine A. Lebel, Carol B. Fox, Alka Shrikhande, James Heym, Eric Schaeffer, Hans Rollema, Yi Lu, Robert S. Mansbach, Leslie K. Chambers, Charles C. Rovetti, David W. Schulz, F. David Tingley, Brian T. O’Neill,

Synthesis and Biological Evaluation

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.