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）外，安非他酮是唯一经FDA批准的治疗方法！ 戒烟。尽管对安非他酮的作用机理进行了大量研究，但特定地点 负责其生物活性的负责人仍未完全理解。抗抑郁作用的机制 似乎与对去甲肾上腺素能神经元的长期影响有关 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的活性而发生的， DAT和NET，各自。体外和体内药理学研究也表明安非他酮是 及其活性代谢产物（2s，3s） - 羟基丙荷是烟碱乙酰胆碱受体的拮抗剂 （NACHR），_41_2 NACHR子类型被识别为最相关的。大多数对安非他酮的研究 作用机制集中在其转运蛋白活性上。但是，我们相信 戒烟（可能是抑郁症）的安非他酮取决于其与多分子的相互作用 目标，我们将其称为活性的Mulitple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C_4132NACHR以及DAT和NET的迭代来实现的。 我们在项目1中的主要目标是根据我们的设计，合成和分析目标化合物 安非他酮MTM。此外，我们实验的数据应导致对MTM的更好理解 并导致开发工具以进一步研究尼古丁成瘾。提议的目标 安非他酮动作是单胺转运蛋白，C_41_2NACHR，甚至可能尚未确定的NACHR 亚型。该计划项目将涉及各种化合物对的影响的系统分析 单胺摄取和NACHR以及化合物对与尼古丁有关的行为的影响 依赖。这项研究将确定目标的混合物，这些目标是该多个目标模型的特征 （MTM）。该项目1的最初具体目的是：（1）设计和合成目标化合物 在该项目中进行单胺摄取研究评估的安非他酮和3-苯基tropane类 项目2中的OT4_2 NACHR和项目3中提出的体内研究； （2）分析初始体外和体内 相互作用的所有三个项目的数据，以选择用于评估的化合物在Advanced In Vivo中 项目3中尼古丁戒断，药物歧视和自我管理的模型旨在评估 这些化合物的潜力是戒烟药物； （3）对完整的数据进行遵守 设置为统计分析，以确定最能与先进的体内研究相关的靶标 为未来发展提出化合物。