SYNTHESIS AND IN VIVO EVALUATION OF NANTENINE ANALOGS

南藤碱类似物的合成和体内评价

• 批准号: 8357185
• 负责人: Wayne Wesley Harding
• 金额: $ 11.92万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357185
• 关键词: Aporphines; Basic Science; Behavioral; Biological Factors; Center for Translational Science Activities; Development; Drug usage; Evaluation; Funding; Goals; Grant; Health; Lead; Modification; Mus; National Center for Research Resources; Physiological; Positioning Attribute; Principal Investigator; Research; Research Infrastructure; Resources; Role; Site; Source; Structure; Structure-Activity Relationship; Surveys; Testing; Therapeutic; Therapeutic Agents; United States National Institutes of Health; Work; analog; base; club drug; cost; design; ecstasy; ecstasy drug dependence; ecstasy overdose; health disparity; in vivo; novel therapeutics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. According to the National Survey on Drug Use and Health over 10 million people have tried the club drug "Ecstasy" (MDMA) at least once in their lifetime. Currrently there are no therapeutically specific agents to treat MDMA addiction and overdose. The natural product (+)-nantenine has been found to antagonize some of the effects of MDMA in vivo and shows promise for the deveopment of well-needed MDMA therapeutics. The long-term goal of this project is to develop therapeutic agents based on nantenine to treat MDMA dependence and overdose. The objective of this exploratory application is to better understand the role of various structural motifs of (+)-nantenine for antagonism of the physiological and behavioral effects of MDMA in mice. The Central Hypothesis of this proposal is that structural modification of nantenine will lead to potent molecules with the ability to antagonize behavioral and physiological effects induced by MDMA in vivo. The rationale of this application is that an understanding of the role/importance of various structural motifs of nantenine on MDMA antagonistic activity in vivo, will provide valuable information for the development of novel therapeutic agents to treat MDMA dependence and overdose based on the (+)-nantenine core structure. We plan to test the central hypothesis and achieve the overall objectives by pursuing the following specific aims: Specific Aim #1: Examine the importance of the chiral center of nantenine in blocking and/or reversing MDMA-induced effects in mice. The working hypothesis of this specific aim is that the chiral center of nantenine is important for in vivo antagonism of MDMA's behavioral and physiological effects. Specific Aim #2: Examine the role of the C-2 site of the (+)-nantenine aporphine core on MDMA-induced behavioral and physiological effects in mice. The working hypothesis of this aim is that the C-2 position of the (+)-nantenine aporphine core is a crucial site for modulation of its MDMA antagonizing effects in vivo. We will chemically synthesize analogs of nantenine and evaluate the ability of the analogs to block/reverse MDMA-induced effects in mice. The completion of this project will allow us to determine structure-activity relationships of nantenine in relation to in vivo MDMA antagonism and lead to the design of potent therapeutics to treat MDMA addiction and overdose.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 根据全国药物使用和健康调查，超过 1000 万人一生中至少尝试过一次俱乐部药物“摇头丸”(MDMA)。目前还没有治疗 MDMA 成瘾和过量用药的特异性药物。天然产物 (+)-nantenine 被发现可以拮抗 MDMA 体内的一些作用，并显示出开发急需的 MDMA 疗法的希望。 该项目的长期目标是开发基于南藤宁的治疗药物，以治疗 MDMA 依赖和过量用药。这一探索性应用的目的是更好地了解 (+)-nantenine 的各种结构基序在拮抗 MDMA 对小鼠的生理和行为影响方面的作用。该提案的中心假设是南藤宁的结构修饰将产生有效的分子，能够拮抗 MDMA 在体内引起的行为和生理效应。本申请的基本原理是，了解南藤宁的各种结构基序对体内 MDMA 拮抗活性的作用/重要性，将为开发基于 (+) 的 MDMA 依赖和过量用药的新型治疗剂提供有价值的信息。 -nantenine核心结构。我们计划通过追求以下具体目标来测试中心假设并实现总体目标：具体目标#1：检查南藤宁的手性中心在阻断和/或逆转 MDMA 诱导的小鼠效应中的重要性。这一具体目标的工作假设是南藤宁的手性中心对于体内拮抗 MDMA 的行为和生理效应非常重要。具体目标#2：检查 (+)-nantenine aporphine 核心的 C-2 位点对 MDMA 诱导的小鼠行为和生理效应的作用。该目标的工作假设是 (+)-nantenine aporphine 核心的 C-2 位置是调节其体内 MDMA 拮抗作用的关键位点。 我们将化学合成南藤宁类似物，并评估该类似物在小鼠中阻断/逆转 MDMA 诱导效应的能力。该项目的完成将使我们能够确定南藤宁与体内 MDMA 拮抗作用的结构-活性关系，并导致设计有效的 治疗 MDMA 成瘾和过量的疗法。