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），安非他酮是唯一FDA批准的治疗！ 戒烟。尽管对安非他酮的作用机制进行了大量的研究， 其生物活性的原因仍然没有完全了解。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通过其在多巴胺和去甲肾上腺素转运蛋白上的活性发生的， DAT和NET。体外和体内药理学研究也表明，安非他酮作为 其活性代谢产物（2S，3S）-羟基安非他酮是烟碱型乙酰胆碱受体拮抗剂 （nAChR），其中_41_2 nAChR亚型被鉴定为最相关。大多数关于安非他酮的研究 作用机制集中在其转运活性上。然而，我们认为， 安非他酮用于戒烟（可能还有抑郁症）取决于它与多种分子的相互作用， 我们称之为活动的多目标模型（MTM）。我们的假设是，临床上 安非他酮的功效是通过与c_4132nAChR以及DAT和NET之一或两者的相互作用来实现的。 我们在项目1中的主要目标是设计，合成和分析目标化合物， 安非他酮此外，从我们的实验数据应导致更好地了解MTM 并导致工具的发展，以进一步研究尼古丁成瘾。建议的目标 安非他酮的作用是单胺转运蛋白，c_41_2nAChR，可能还有其他尚未确定的nAChR 亚型该计划项目将涉及系统分析各种类型的化合物对 单胺摄取和nAChRs以及化合物对尼古丁相关行为的影响 依赖本研究将确定作为该多目标模型特征的目标混合物 （MTM）。本项目一的初步具体目标是：（1）从天然产物中设计合成目标化合物， 安非他酮和3-苯基托烷类，用于本项目单胺摄取研究的评价，以及 在项目2和项目3中提出的体内研究中的α 4_2 nAChR;（2）分析初始体外和体内研究 来自所有三个项目的数据，在一个交互过程中选择化合物进行高级体内评价 尼古丁戒断、药物歧视和自我给药模型，旨在评估 这些化合物作为戒烟药物的潜力;以及（3）受试者的完整数据 进行统计分析，以确定与高级体内研究最相关的靶点， 为未来的发展提出化合物。