Nicotine, which is the major psychoactive constituent of tobacco, is one of the most widely used substances of abuse. In recent years it has become well established that the mechanism of action of nicotine on the central nervous system is mediated via nicotinic receptors which are distinct from those at the neuromuscular junction and appear to exist in multiple subtypes. The overall objective this proposal is aimed at is the molecular characterization of brain sites for nicotine action.
The specific aims of the proposal are as follows: 1. Purification of the brain nicotinic receptor proteins by affinity and immunoaffinity chromatography. Amino acid sequence will be performed on nicotinic recognition sites. 2. Structure-Activity studies with newly synthesized nicotinic agonists and of alkylaminoalkyl alcohols will be synthesized and tested pharmacologically and for receptor binding. 3. Structure-Activity studies with bridged analogues of nicotine. The compounds will be screened for their psychotropic and cardiovascular effects as well as for 3H-nicotine and 3H-methylcarbamycholine binding. 4. Studies aimed at determining the mode of mecamylamine's antagonism to nicotine. Characterization and purification of the mecamylamine binding site in rat brain; a site which is believed to be associated with an ionic channel. 5. Characterization and identification of the nicotinic receptor by affinity labeling. A number of 3H-labeled affinity ligands of nicotine will be synthesized and used to label the nicotine receptor proteins. Such studies should contribute a better understanding of the chemical and psychopharmacologic nature of nicotine's action; and it is hoped that the structure-activity studies with novel agonists and antagonists may provide a basis for the treatment of the tobacco habit.
