Nicotine abuse leads to approximately 430,000 deaths a year in the United States. Even though most smokers want to quit, only 3% can do so without the use of other intervention. Both the psychological and physiological effects of tobacco smoke (smoking) are attributed to nicotine. The goal of this application is to discover and develop medications for the treatment of smokers. However, we expect that the compounds developed will also serve as biochemical probes useful in gaining a better understanding of the biochemical and molecular mechanisms of nicotine addition and withdrawal. Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central and peripheral nervous systems including several regions of the brain. Two major classes of nAChRs, alpha4beta2 and alpha7, have been identified in rat and human brains. The possibility exists that specific subtypes mediate specific functions, especially as this relates to nicotine addiction. Thus, the availability of a variety of ligands that bind with high affinity and selectivity for each subtype class is needed. It is also desirable to have both agonists and antagonists since the role of nAChRs in addiction is not known. Epibatidine is a nicotinic agonist whose biological effects appear to be mediated largely by alpha4beta2 nAChRs. Methyllycaconitine (MLA) is the most potent non-peptide competitive antagonists at U-7 neuronal nAChRs thus far reported. The high potency of epibatidine for uAP2 nAChRs and the potency and selectivity of MILA toward the brain alpha7 receptor makes these agents very useful lead compounds for the development of new ligands for studying these nicotinic subtypes. The objective of the research proposed in this application is to conduct SAR studies to develop novel epibatidine and MILA analogs for probing (alpha4beta2 and alpha7 nicotinic receptors. Pharmacological profiles of compounds identified as potent and/or selective for one of the subtypes will be examined for modulation of rodent behavior (antinociception and motor activity), for their ability to substitute for nicotine in rat discrimination, and for their ability to change nicotine self-administration in rats. Selected compounds will be studied at various alpha,beta and alpha7 combinations expressed in Xenopus oocytes to determine the nAChR subtype binding and functional profiles. Since little is known about the in vivo disposition of nAChR both before and after chronic nicotine exposure, PET and SPECT ligands will be developed to identify specific brain regions involved and to help resolve the role various nAChR subtypes play in the addiction process.
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