SYNTHESIS AND IN VIVO EVALUATION OF NANTENINE ANALOGS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 根据全国毒品使用和健康调查，超过1000万人一生中至少尝试过一次俱乐部毒品“摇头丸”（MDMA）。目前还没有治疗MDMA成瘾和过量的治疗特异性药物。已发现天然产物（+）-nantenine在体内拮抗MDMA的某些作用，并显示出开发急需的MDMA治疗剂的前景。 该项目的长期目标是开发基于nantenine的治疗药物，以治疗MDMA依赖和过量。该探索性应用的目的是更好地了解（+）-nantenine的各种结构基序对MDMA在小鼠中的生理和行为效应的拮抗作用。这一建议的中心假设是，南替宁的结构修饰将导致具有拮抗MDMA在体内诱导的行为和生理效应的能力的有效分子。本申请的基本原理是，了解南替宁的各种结构基序对体内MDMA拮抗活性的作用/重要性，将为基于（+）-南替宁核心结构开发治疗MDMA依赖和过量的新型治疗剂提供有价值的信息。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nantenine的手性中心在阻断和/或逆转小鼠中MDMA诱导的作用中的重要性。这一特定目标的工作假设是，南替宁的手性中心对于MDMA的行为和生理效应的体内拮抗作用是重要的。具体目标#2：检查（+）-南天宁阿朴啡核心的C-2位点对小鼠中MDMA诱导的行为和生理效应的作用。这一目标的工作假设是，（+）-nantenine阿朴啡核心的C-2位是调节其体内MDMA拮抗作用的关键位点。 我们将化学合成nantenine的类似物，并评估类似物阻断/逆转小鼠中MDMA诱导效应的能力。该项目的完成将使我们能够确定nantenine与体内MDMA拮抗作用的结构-活性关系，并设计有效的药物组合物。 治疗MDMA成瘾和过量的药物。

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.