Synthesis of Bupropion Analogs, Including Possible Metabolites and 3-Phenyltropan

除了尼古丁替代疗法(NRT)，安非他酮是FDA批准的唯一治疗！ 戒烟。尽管对安非他酮的作用机制进行了大量研究，但特定的部位 对其生物活性负有责任的人仍不完全清楚。抗抑郁作用机制研究进展 似乎与对去甲肾上腺素能神经元的长期影响有关，其中有一些贡献 多巴胺能神经元。这些变化可能是通过它在多巴胺和去甲肾上腺素转运体上的活性而发生的， 分别为DAT和NET。体外和体内药理研究也表明安非他酮是 其活性代谢物(2S，3S)-羟基安非他酮是烟碱型乙酰胆碱受体的拮抗剂 (NAChR)，其中_41_2 nAChR亚型被认为是最相关的。大多数关于安非他酮的研究 作用机制主要集中在其转运蛋白的活性上。然而，我们相信，这种药物的临床疗效 安非他酮用于戒烟(和可能的抑郁)依赖于它与多个分子的相互作用 目标，我们称之为活动的多目标模型(MTM)。我们的具体假设是临床上 安非他酮的药效是通过与C4132nAChR和/或DAT和Net的迭代作用实现的。 我们在项目1的主要目标是设计、合成和测试目标化合物，基于我们的 安非他酮MTM。此外，我们的实验数据应该有助于更好地理解MTM 并导致进一步研究尼古丁成瘾的工具的开发。建议的目标 安非他酮的作用是单胺转运体、c_41_2nAChR和其他可能尚未确定的nAChR 子类型。该计划项目将包括系统分析各种类型的化合物对 单胺摄取和nAChRs及其化合物对尼古丁相关行为的影响 依赖。这项研究将确定作为多目标模型的特征的目标的混合 (MTM)。这个项目一的最初的具体目标是：(1)从目标化合物中设计和合成 本项目单胺摄取研究中用于评价的安非他酮和3-苯基托烷类别以及 项目2中的OT4_2 nAChR和项目3中提出的体内研究；(2)初步的体外和体内分析 来自所有三个项目的数据，以选择用于体内高级评估的化合物的迭代过程 旨在评估项目3中尼古丁戒断、药物歧视和自我给药的模型 这些化合物作为戒烟药物的潜力；以及(3)研究完整的数据 进行统计分析，以确定与先进的活体研究和 提出化合物的未来发展方向。

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, respectivly. 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 _41_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 Mulitple Target Model (MTM) of activity. Our specific hypothesis is that clinical efficacy 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 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 c_41_2nAChR, and possibly other as yet undefined nAChR subtypes. This program project will involve systematic analysis of effects of various types of compounds on monoamine uptake and nAChRs and of 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 ot4_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 interative 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.