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

安非他酮类似物的合成，包括可能的代谢物和 3-苯托潘

• 批准号: 7620451
• 负责人: FRANK Ivy CARROLL
• 金额: $ 16.79万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620451
• 关键词: Affinity; Antidepressive Agents; Behavior; Behavioral; Binding; Biological; Biological Assay; Brain; Bupropion; Class; Classification; Data; Data Analyses; Data Set; Decision Trees; Dependence; Development; Dopamine; Evaluation; Future; In Vitro; Lead; Long-Term Effects; Mental Depression; Methods; Modeling; Molecular Target; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Norepinephrine; Numbers; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Process; Property; Rattus; Relative (related person); Research; Selection Criteria; Self Administration; Serotonin; Site; Smoker; Structure; Study Section; Synaptosomes; System; analog; base; clinical efficacy; design; desire; dopamine transporter; dopaminergic neuron; drug discrimination; in vivo; in vivo Model; monoamine; nicotine replacement; noradrenaline transporter; noradrenergic; programs; receptor; research study; smoking cessation; tool; tool development; uptake

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.

除了尼古丁替代疗法 (NRT) 之外，安非他酮是 FDA 批准的唯一治疗方法！ 戒烟。尽管对安非他酮的作用机制进行了大量研究，但具体位点 其生物活性的负责机制尚未完全清楚。抗抑郁作用机制 似乎与去甲肾上腺素能神经元的长期影响有关，其中一些贡献来自 多巴胺能神经元。这些变化可能是由于其在多巴胺和去甲肾上腺素转运蛋白上的活性而发生的， 分别为 DAT 和 NET。体外和体内药理学研究也表明安非他酮 及其活性代谢物 (2S,3S)-羟基安非他酮是烟碱乙酰胆碱受体的拮抗剂 (nAChR)，其中 _41_2 nAChR 亚型被确定为最相关。大多数研究都针对安非他酮 作用机制集中于其转运蛋白活性。但我们相信临床疗效 安非他酮对戒烟（以及可能的抑郁症）的作用取决于其与多种分子的相互作用 目标，我们将其称为活动的多目标模型 (MTM)。我们的具体假设是临床 安非他酮的功效是通过与 c_4132nAChR 以及 DAT 和 NET 之一或两者的迭代来实现的。 我们项目 1 的主要目标是根据我们的研究成果设计、合成和分析目标化合物。 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 并导致开发进一步调查尼古丁成瘾的工具。拟议目标 安非他酮的作用是单胺转运蛋白、c_41_2nAChR，以及可能其他尚未定义的 nAChR 亚型。该计划项目将涉及系统分析各类化合物对 单胺摄取和 nAChR 以及化合物对尼古丁相关行为的影响 依赖性。这项研究将确定作为多目标模型特征的目标混合 （MTM）。该项目1的初步具体目标是：（1）从原料中设计并合成目标化合物。 安非他酮和 3-苯基托烷类用于评估本项目的单胺吸收研究以及 项目2中的ot4_2 nAChR和项目3中提出的体内研究； (2) 初步体外和体内分析 来自所有三个项目的交互过程中的数据，用于选择用于高级体内评估的化合物 项目 3 中的尼古丁戒断、药物歧视和自我管理模型旨在评估 这些化合物作为戒烟药物的潜力； (3) 提供完整的数据 设置统计分析以确定与高级体内研究最相关的目标 提出未来开发的化合物。