In response to PAR-04-009, we are pleased to submit this application whose overall goal is to find a better smoking cessation drug. 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 sites responsible for its biological activity are still not fully understood. The mechanism of antidepressant action appears to be associated with long-term effects on noradrenergic neurons with some contribution from dopaminergic neurons. These changes likely occur by its activity at the dopamine and norepinephrine transporters, DAT and NET, respectively. In vitro and in vivo pharmacological studies also indicate bupropion is an antagonist of nicotinic acetylcholine receptors (nAChR), with the a4?2 nAChR subtype identified as the most relevant. Most research into bupropion's mechanism of action has focused on its transporter activity. However, we believe the clinical efficacy of bupropion for smoking cessation (and possibly depression) depends on its interaction with multiple molecular targets, which we term a Multiple Target Model (MTM) of activity. Our specific hypothesis is that clinical efficacy of bupropion is achieved via interactions with the a4?2 nAChR and either or both the DAT and NET. We also present preliminary studies that indicate the (2S,3S)-hydroxybupropion metabolite has a4?2 nAChR activity as well as dopamine (DA) and norepinephrine (NE) uptake inhibition activity, strongly suggesting this metabolite plays a major role in bupropion's activity as a smoking cessation drug. Our main objective is to develop better smoking cessation medication by synthesizing and testing compounds based on the bupropion MTM. In addition, data from our experiments should lead to a better understanding of our MTM and lead to the development of tools to further investigate nicotine addiction. This application brings together a group of experienced investigators from three separate organizations. Dr. F. Ivy Carroll (Research Triangle Inst.), Dr. Ronald J. Lukas (Barrow Neurological Inst.), and Dr. M. Imad Damaj (Virginia Commonwealth Univ.) have extensive experience in organic and medicinal chemistry, molecular pharmacology, animal behavioral pharmacology, and drug abuse research. The research is split into three projects, one from each organization, coordinated to reach our goals and objectives. In Project 1, the compounds will be designed, synthesized, and evaluated for their DA, 5-HT, and NE uptake activity. In Project 2 the nAChR subtype functional activity profile of the compounds will be determined. In Project 3 the compounds will be evaluated for their ability to antagonize the effects of nicotine in the tail-flick and hot-plate antinociception tests, locomotor activity, and hypothermia. The potential clinical utility of select compounds will be assessed using drug discrimination, withdrawal, and self-administration tests. The outcome of these studies will be the development of potential new pharmacotherapies to treat nicotine addiction. ? ? PROJECT 1: """"""""Synthesis of Bupropion Analogs, Including Possible Metabolites and 3-Phenyltropane Analogs, and in Vitro Evaluation of Drug Effects at Monoamine Neurotransmitter Transporters"""""""" ? ? (PI - Dr. Frank Carroll). ? ? DESCRIPTION (provided by applicant): 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 sites responsible for its biological activity are still not fully understood. The mechanism of antidepressant action appears to be associated with longterm effects on noradrenergic neurons with some contribution from dopaminergic neurons. These changes likely occur by its activity at the dopamine and norepinephrine transporters, DAT and NET, respectively. In vitro and in vivo pharmacological studies also indicate bupropion as well as its active metabolite (2S, 3S)-hydroxybupropion is an antagonist of nicotinic acetylcholine receptors (nAChR), with the a4?2 nAChR subtype identified as the most relevant. Most research into bupropion's mechanism of action have focused on its transporter activity. However, we believe the clinical efficacy of bupropion for smoking cessation (and possibly depression) depends on its interaction with multiple molecular targets, which we term a Multiple Target Model (MTM) of activity. Our specific hypothesis is that clinical efficacy of bupropion is achieved via interactions with the a4?2 nAChR and either or both the DAT and NET. Our main objective in Project 1 is to design, synthesize and assay targets compounds based on our bupropion MTM. In addition, data from our experiments should lead to a better understanding of the MTM and lead to the development of tools to further investigate nicotine addiction. The proposed targets of bupropion action are monoamine transporters, the a4?2 nAChR, and possibly other as yet undefined nAChR subtypes. This project will involve systematic analysis of the effects of various types of compounds on monoamine uptake and nAChRs and of the effects of the compounds on behaviors related to nicotine dependence. 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 the bupropion and 3-phenyltropane classes for evaluation in monoamine uptake studies in this project as well as a4?2 nAChR in Project 2 and in vivo studies proposed in Project 3; (2) to analyze initial in vitro and in vivo data from all three projects in an interactive process to select compounds for evaluation in advanced in vivo models of nicotine withdrawal, drug discrimination, and self-administration in Project 3 designed to assess the potential of these compounds to be smoking cessation medications; and (3) to subject the complete data set to a statistical analysis to determine the targets that best correlate with the advanced in vivo studies and to propose the compounds for future development. ? ?
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