3,5-Bicyclic aryl piperidines: A novel class of a4b2 neuronal nicotinic receptor partial agonists for smoking cessation Jotham W. Coe, * Paige R. Brooks, Michael C. Wirtz, Crystal G. Bashore, Krista E. Bianco, Michael G. Vetelino, Eric P. Arnold, Lorraine A. Lebel, Carol B. Fox, F. David Tingley, III, David W. Schulz, Thomas I. Davis, Steven B. Sands, Robert S. Mansbach, Hans Rollema and Brian T. OÕNeill Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA Received 17 June 2005; revised 5 August 2005; accepted 9 August 2005 Available online 19 September 2005 Abstract—3,5-Bicyclic aryl piperidines are a new class of high-affinity a4b2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the a4b2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation. Ó 2005 Elsevier Ltd. All rights reserved. More than half of the 1.25B current smokers worldwide will die from tobacco-related illness. 1 Despite this star- tling fact and the undisputed connection between tobac- co use and disease, global smoking rates continue to rise. Usually beginning as an innocent act, smoking becomes habitual owing to the powerful dependence-producing effects of nicotine. 2 Unfortunately, the vast majority of smokers find tobacco dependence difficult to overcome, with >95% of unaided quit attempts ending in failure. Smoking initiates and maintains a cycle of neurochemi- cal events via nicotineÕs action as an agonist 3 of neuro- nal nicotinic acetylcholine receptors (nAChRs). 4 A number of studies point to the a4b2 subtype of the nAChRs as important to the dependence-producing ef- fects of nicotine. 5 These reports have been recently bol- stered by findings that certain a4 subtype mutants render transgenic mice hypersensitive to nicotine 6 and that b2 expression in the ventral tegmental area of the mesolimbic dopamine system of b2-deletion mutants restores wild type function in response to nicotine. 7 Nicotine exposure from tobacco triggers the release of dopamine in the mesolimbic dopamine system. 8 As nicotineÕs concentration declines, the elevated dopamine levels subside, signaling the urge to smoke. 9 Lower dopaminergic tone from abstinence induces craving and withdrawal syndrome. 10,11 Hypothetically nicotine mediates reward and satisfaction through dopamine re- lease, thereby providing relief from withdrawal and craving. 12 Peak and trough levels, or the overall dopami- nergic tone, therefore, are managed through smoking. These fundamental effects of nicotine at nAChRs govern many subsequent responses, including receptor desensi- tization and upregulation and the dependence liability that results. Although therapeutic advances have improved long- term quit rates compared to placebo in clinical studies, these rates remain disappointingly low. 13 Nicotine replacement therapy provides controlled-release nicotine and acts to suppress craving and withdrawal from smoking cessation, but it does not prevent activation of nAChRs by nicotine from smoking. 14 Bupropion has been shown to dampen the urge to smoke, but it per- mits a response to smoking. 15,16 Studies with nicotine vaccines that sequester nicotine to prevent nicotinic acti- vation show promise, but these vaccines theoretically fail to address craving and withdrawal. 17 We reasoned that a dual agent that relieved the craving and withdrawal syndrome while simultaneously attenuat- ing the nicotine-induced effects of smoking could deliver 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.08.035 Keywords: a4b2 nicotinic receptor; nAChR; Partial agonist; Smoking cessation; Alkaloid; Varenicline. * Corresponding author. Tel.: +1 860 441 3271; fax: +1 860 686 0013; e-mail: jwcoe@pfizer.com Bioorganic & Medicinal Chemistry Letters 15 (2005) 4889–4897