The Caltech-Boulder-Targacept National Cooperative Drug Discovery and Development Group (NCDDDG) continues to be motivated by the hypothesis that successful smoking cessation compounds can selectively target just one or a few nicotinic acetylcholine receptor (nAChR) combinations. Nicotine addiction begins with the activation of these receptors, which are ligand-gated channels. Progress in this NCDDG and around the world during the 2005-2010 Project Period provided additional knowledge about the range of homo- and hetero-pentameric subtypes that do exist in the brain;about their localization;and about their specific roles in the constellation of phenomena that comprise nicotine addiction (tolerance, dependence, sensitization, and goal-seeking behavior). Nonetheless, knowledge remains partial, especially about the long-term effects of both nicotine and smoking cessation drugs. The 2010-2015 Project Period provides an iterative series of experiments to test hypotheses in these areas. (1) The NCDDDG will use accumulating knowledge to optimize lead compounds for smoking cessation. We will devote the first 2 yr of the Project Period to three lead compounds that emphasize a6-oriented and/or a4-oriented activity: varenicline, TCD-1010, and one other compound to be chosen by the Executive Committee. The compounds are expected to exhibit varying ratios of a6* to a4* activity. All these compounds will be at least partial agonists. We expect that all compounds will also desensitize a4* nAChRs;a6* desensitization will be studied in detail in Project 3. (2) It is also likely that successful smoking cessation compounds will themselves produce long-term changes in these target nAChRs. Therefore Projects 2 and 3 will use mouse models to explore possible upregulation, an adaptive change in nAChRs caused by chronic exposure to lead compounds. (3) The iterative experiments will, in turn, lead to synthesis of new compounds at Targacept (Project 1), and further testing during the final three yr of the 2010-2015 Project Period. This scientific approach will enable the Group, as well as other groups throughout the world, to optimize and develop lead compounds for smoking cessation. (4) While pursuing these goals in parallel, we intend to continue publishing all of our studies according to the usual standards that have characterized research in academic neuroscience.

Public Health Relevance

Roughly 400,000 Americans and roughly 4,000,000 people worldwide die annually of the sequelae to smoking tobacco smoking. This project attempts to develop new principles and therapeutics for smoking cessation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19DA019375-09
Application #
8534072
Study Section
Special Emphasis Panel (ZMH1-ERB-C (03))
Program Officer
Rapaka, Rao
Project Start
2004-12-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$734,650
Indirect Cost
$120,173
Name
California Institute of Technology
Department
None
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon et al. (2014) Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function *6* nAChRs. J Neurochem 129:315-27
Limapichat, Walrati; Dougherty, Dennis A; Lester, Henry A (2014) Subtype-specific mechanisms for functional interaction between ?6?4* nicotinic acetylcholine receptors and P2X receptors. Mol Pharmacol 86:263-74
Eaton, J Brek; Lucero, Linda M; Stratton, Harrison et al. (2014) The unique *4+/-*4 agonist binding site in (*4)3(*2)2 subtype nicotinic acetylcholine receptors permits differential agonist desensitization pharmacology versus the (*4)2(*2)3 subtype. J Pharmacol Exp Ther 348:46-58
Wageman, Charles R; Marks, Michael J; Grady, Sharon R (2014) Effectiveness of nicotinic agonists as desensitizers at presynaptic *4*2- and *4*5*2-nicotinic acetylcholine receptors. Nicotine Tob Res 16:297-305
Henderson, Brandon J; Srinivasan, Rahul; Nichols, Weston A et al. (2014) Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. J Gen Physiol 143:51-66
O'Neill, Heidi C; Laverty, Duncan C; Patzlaff, Natalie E et al. (2013) Mice expressing the ADNFLE valine 287 leucine mutation of the ýý2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function. Pharmacol Biochem Behav 103:603-21
Marks, Michael J (2013) Genetic matters: thirty years of progress using mouse models in nicotinic research. Biochem Pharmacol 86:1105-13
Ortiz, Nick C; O'Neill, Heidi C; Marks, Michael J et al. (2012) Varenicline blocks ?2*-nAChR-mediated response and activates ?4*-nAChR-mediated responses in mice in vivo. Nicotine Tob Res 14:711-9
Grady, Sharon R; Wageman, Charles R; Patzlaff, Natalie E et al. (2012) Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include ýý5 or ýý6 subunits and that mediate synaptosomal neurotransmitter release. Neuropharmacology 62:1935-43
Xiao, Cheng; Srinivasan, Rahul; Drenan, Ryan M et al. (2011) Characterizing functional ýý6ýý2 nicotinic acetylcholine receptors in vitro: mutant ýý2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells. Biochem Pharmacol 82:852-61

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