Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation.
Most smokers repeatedly fail in their attempts to stop smoking because of the addictive nature of the nicotine in tobacco products. Nicotine dependence is probably mediated through the activation of multiple subtypes of neuronal nicotinic acetylcholine receptor (nAChR), among which the mesolimbic alpha(4)beta(2) subtype has a pivotal role. Here, we discuss the rationale for and the design of alpha(4)beta(2) nAChR partial agonists as novel treatments for tobacco addiction. Such agents are expected to exhibit a dual action by sufficiently stimulating alpha(4)beta(2)-nAChR-mediated dopamine release to reduce craving when quitting and by inhibiting nicotine reinforcement when smoking. Potent and selective alpha(4)beta(2) nAChR partial agonists that exhibit dual agonist and antagonist activity in preclinical models can be identified. The validity of this approach is demonstrated by the clinical efficacy of the alpha(4)beta(2) nAChR partial agonist varenicline, which has significantly better quit rates than do other treatments and offers a new option for smoking cessation pharmacotherapy.
Rollema
Hans
H
Department of Neuroscience Biology, Pfizer Global Research and Development, Groton, CT 06340, USA. hans.rollema@pfizer.com
Coe
Jotham W
JW
Chambers
Leslie K
LK
Hurst
Raymond S
RS
Stahl
Stephen M
SM
Williams
Kathryn E
KE
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000378:metabolism*; D016540:Smoking Cessation; D014029:Tobacco Use Disorder / Q000188:drug therapy*; D016896:Treatment Outcome; D000068580:Varenicline
D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D000068580:Varenicline