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（由申请提供）：为了响应PAR-04-009，我们很高兴提交此申请，其总体目标是找到更好的戒烟药物。除了尼古丁替代疗法（NRT）外，安非他酮是唯一可以戒烟的FDA批准治疗方法。尽管对安非他酮的作用机理进行了大量研究，但仍未完全了解负责其生物活性的特定部位。抗抑郁作用的机制似乎与多巴胺能神经元的某些贡献有关对甲肾上腺神经元的长期影响。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（DAT和NET）的活性而发生的。体外和体内药理学研究还表明，安非他酮是烟碱乙酰胆碱受体（NACHR）的拮抗剂，其A4¿2NACHR亚型被鉴定为最多。相关的。对安非他酮作用机理的大多数研究都集中在其转运蛋白活性上。但是，我们认为安非他酮在戒烟（和可能的抑郁症）中的临床效率取决于其与多个分子靶标的相互作用，我们将其称为活性的多个目标模型（MTM）。我们的具体假设是，安非他酮的临床效率是通过与A4€2 NACHR以及DAT和NET的相互作用来实现的。我们还提出了表明（2s，3s） - 羟基替代代谢物具有a4¿2nACHR活性以及多巴胺（DA）和去甲肾上腺素（NE）抑制活性，强烈暗示这种代谢物在Bupropropropion的活性中发挥着重要的作用。我们的主要目标是通过基于安非他酮MTM的合成和测试化合物来开发更好的戒烟药物。此外，我们实验的数据应导致对我们的MTM有更好的了解，并导致开发工具，以进一步研究尼古丁成瘾。该应用程序汇集了来自三个独立组织的一群经验丰富的调查员。 F. Ivy Carroll博士（研究三角研究所），Ronald J. Lukas博士（Barrow Neurological Inst。）和M. Imad Damaj博士（Virginia Commonwealth Univ。）在有机和医学化学，分子药理学，动物行为药理和药物滥用研究方面具有丰富的经验。该研究分为三个项目，一个从每个组织进行协调，以实现我们的目标。在项目1中，将对其DA，5-HT和NE摄取活性进行设计，合成和评估化合物。在项目2中，将确定化合物的NACHR亚型功能活动曲线。在项目3中，将评估化合物的能力，以拮抗尼古丁在尾板和热板的抗热感受测试，运动活性和体温过低的作用中。精选化合物的潜在临床实用性将使用药物歧视，戒断和自我给药测试评估。这些研究的结果将是开发潜在的新药物治疗尼古丁成瘾的药物。 项目1：“安非他酮类似物的合成，包括可能的代谢产物和3-苯基趋烷类似物，以及对单胺神经递质转运蛋白转运蛋白的药物作用的体外评估” （PI-弗兰克·卡罗尔博士）。 描述（由适用提供）：除了尼古丁替代疗法（NRT）以外，安非他酮是唯一允许FDA批准的戒烟治疗方法。尽管对安非他酮的作用机理进行了大量研究，但仍未完全了解负责其生物活性的特定部位。抗抑郁作用的机制似乎与多巴胺能神经元的某些贡献有关对去甲肾上腺素能神经元的长期影响。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（DAT和NET）的活性而发生的。体外和体内药理学研究还表明安非他酮及其活性代谢产物（2s，3s） - 羟基抑制剂是烟碱乙酰胆碱受体（NACHR）的拮抗剂，其a4¿2NACHR子类型确定为最相关的NACHR子类型。对安非他酮作用机理的大多数研究都集中在其转运蛋白活性上。但是，我们认为安非他酮在戒烟（和可能的抑郁症）中的临床效率取决于其与多个分子靶标的相互作用，我们将其称为活性的多个目标模型（MTM）。我们的具体假设是，安非他酮的临床效率是通过与A4€2 NACHR以及DAT和NET的相互作用来实现的。我们在项目1中的主要目标是根据我们的安非他酮MTM设计，合成和分析目标化合物。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添加。拟议的安非他酮作用的靶标是单胺转运蛋白，A4¿2NACHR，可能是其他尚未定义的NACHR亚型。该项目将涉及对各种化合物对单胺摄取和NACHR的影响的系统分析，以及化合物对与尼古丁依赖性相关的行为的影响。这项研究将确定目标多个目标模型（MTM）特征的目标的混合物。该项目1的最初具体目的是：（1）在该项目中的单胺摄取研究中设计和合成来自安非他酮和3-苯基趋烷类的目标化合物，以及项目2中的A4¿2NACHR，并在项目3中提出了体内研究； （2）在交互过程中分析来自所有三个项目的初始体外和体内数据，以选择化合物，以评估尼古丁戒断，药物歧视和自我管理的先进体内模型，旨在评估这些化合物的潜力，以评估这些化合物的潜在吸烟药物； （3）将完整的数据集审向统计分析，以确定最能与先进的体内研究相关的靶标，并提出化合物以供未来开发。