Development of Pharmacotherapies for Nicotine Addiction

尼古丁成瘾药物疗法的开发

• 批准号: 6857408
• 负责人: FRANK Ivy CARROLL
• 金额: $ 64.98万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6857408
• 关键词: Development; Pharmacotherapies; Nicotine; Addiction

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：作为对PAR-04-009的回应，我们很高兴提交此申请，其总体目标是寻找更好的戒烟药物。除了尼古丁替代疗法（NRT），安非他酮是唯一获得fda批准的戒烟疗法。尽管对安非他酮的作用机制进行了大量研究，但其生物活性的具体位点仍未完全了解。抗抑郁作用的机制似乎与多巴胺能神经元对去甲肾上腺素能神经元的长期影响有关。这些变化可能是由其在多巴胺和去甲肾上腺素转运体DAT和NET上的活性引起的。体外和体内药理学研究也表明，安非他酮是尼古丁乙酰胆碱受体（nAChR）的拮抗剂，其中a4¿2 nAChR亚型被认为是最相关的。大多数关于安非他酮作用机制的研究都集中在它的转运体活性上。然而，我们认为安非他酮对戒烟（可能还有抑郁症）的临床疗效取决于它与多个分子靶点的相互作用，我们称之为多靶点模型（MTM）的活性。我们的具体假设是，安非他酮的临床疗效是通过与a4¿2 nAChR、DAT和NET或两者的相互作用来实现的。我们还提出了初步研究表明(2S,3S)-羟基安非他酮代谢物具有a4¿2 nAChR活性以及多巴胺（DA）和去甲肾上腺素（NE）摄取抑制活性，强烈表明该代谢物在安非他酮作为戒烟药物的活性中起主要作用。我们的主要目标是通过合成和测试基于安非他酮MTM的化合物来开发更好的戒烟药物。此外，我们的实验数据应该有助于更好地理解我们的MTM，并导致进一步研究尼古丁成瘾的工具的开发。这个应用程序汇集了一组经验丰富的调查员从三个不同的组织。F. Ivy Carroll博士（三角研究所）、Ronald J. Lukas博士（巴罗神经学研究所）和M. Imad Damaj博士（弗吉尼亚联邦大学）在有机化学和药物化学、分子药理学、动物行为药理学和药物滥用研究方面拥有丰富的经验。研究分为三个项目，每个组织一个，协调以达到我们的目标和目的。在项目1中，将设计、合成这些化合物，并评估它们的DA、5-羟色胺和NE摄取活性。在项目2中，将确定化合物的nAChR亚型功能活性谱。在项目3中，这些化合物将在甩尾和热板抗感觉试验、运动活动和低温试验中评估其对抗尼古丁影响的能力。所选化合物的潜在临床效用将通过药物鉴别、停药和自我给药试验进行评估。这些研究的结果将是开发潜在的治疗尼古丁成瘾的新药物疗法。