Other than nicotine replacement therapy (NRT), bupropion is the only FDA-approved treatment for !smoking cessation. Despite significant research into bupropion's mechanism of action, the specific sitesresponsible for its biological activity are still not fully understood. The mechanism of antidepressant actionappears to be associated with long-term effects on noradrenergic neurons with some contribution fromdopaminergic neurons. These changes likely occur by its activity at the dopamine and norepinephrine transporters,DAT and NET, respectivly. In vitro and in vivo pharmacological studies also indicate bupropion aswell as its active metabolite (2S,3S)-hydroxybupropion is an antagonist of nicotinic acetylcholine receptors(nAChR), with the _41_2 nAChR subtype identified as the most relevant. Most research into bupropion'smechanism of action have focused on its transporter activity. However, we believe the clinical efficacy ofbupropion for smoking cessation (and possibly depression) depends on its interaction with multiple moleculartargets, which we term a Mulitple Target Model (MTM) of activity. Our specific hypothesis is that clinicalefficacy of bupropion is achieved via iteractions with the c_4132nAChR and either or both the DAT and NET.Our main objective in Project 1 is to design, synthesize and assay targets compounds based on ourbupropion MTM. In addition, data from our experiments should lead to a better understanding of the MTMand lead to the development of tools to further investigate nicotine addiction. The proposed targets ofbupropion action are monoamine transporters, the c_41_2nAChR, and possibly other as yet undefined nAChRsubtypes. This program project will involve systematic analysis of effects of various types of compounds onmonoamine uptake and nAChRs and of effects of the compounds on behaviors related to nicotinedependence. This study will determine the mixture of targets that are features of this Multiple Target Model(MTM). The initial specific aims of this Project 1 are: (1) to design and synthesize target compounds from thebupropion and 3-phenyltropane classes for evaluation in monoamine uptake studies in this project as well asot4_2 nAChR in Project 2 and in vivo studies proposed in Project 3; (2) to analyze initial in vitro and in vivodata from all three projects in an interative process to select compounds for evaluation in advanced in vivomodels of nicotine withdrawal, drug discrimination, and self-administration in Project 3 designed to assessthe potential of these compounds to be smoking cessation medications; and (3) to subject the complete dataset to a statistical analysis to determine the targets that best correlate with the advanced in vivo studies andto propose the compounds for future development.
Showing the most recent 10 out of 22 publications
