Synthesis and Evaluation of Aporphines as MDMA Antagonists.

描述（由申请人提供）：MDMA（“摇头丸”）是一种普遍滥用的药物，特别是在人口中的年轻人中。MDMA的使用与急性生理效应有关，其中包括热疗的发展，这反过来可能导致严重的器官损伤。MDMA具有神经毒性，滥用该药物可导致严重的认知和心理损害。此外，有证据表明反复使用MDMA会产生依赖性。目前，对一种治疗药物的需求尚未得到满足，以对抗MDMA的不良影响。本项目的目的是阐明我们的先导分子(+)-nantenine的结构特征，这是拮抗MDMA行为和生理效应所必需的。我们将验证(+)-nantenine的结构修饰将产生新型阿波啡MDMA拮抗剂的中心假设。为了验证这一假设，我们将进行一项涉及两个特定目标的体内SAR研究。在第一个具体目标中，我们将在药物鉴别实验和热疗实验中研究纳米汀芳香环上取代基对其拮抗mdma诱导作用的影响。对于第二个具体目标，取代基在纳米汀的N6位置的作用将被类似地评估。类似物将在中枢神经系统受体筛选中进行评估，以描述可能适合MDMA拮抗的受体组合策略。公共卫生相关性：这项研究通过允许识别和开发新的分子来对抗设计药物“摇头丸”的作用，对人类健康产生积极影响。

DESCRIPTION (provided by applicant): MDMA ("Ecstasy") is a popular drug of abuse especially among youth in the population. Use of MDMA is associated with acute physiological effects among which is the development of hyperthermia, which in turn may lead to serious organ damage. MDMA is neurotoxic and severe cognitive and psychological damage can result from abuse of the drug. Furthermore, there is evidence that dependence can develop with repeated use of MDMA. There is an unmet medical need for a therapeutic agent to combat the adverse effects of MDMA at this time. The goal of this project is to elucidate structural features of our lead molecule (+)-nantenine, which are required for antagonism of behavioral and physiological effects of MDMA. We will test the central hypothesis that structural modification of (+)-nantenine will yield novel aporphine MDMA antagonists. To test this hypothesis we will engage an in vivo SAR study involving two specific aims . In the first specific aim we will examine the effects of replacement of substituents on the aromatic rings of nantenine on their ability to antagonize MDMA-induced effects in a drug discrimination assay and hyperthermia assay. For the second specific aim the role of substituents at the N6 position of nantenine will be similarly evaluated. Analogs will be evaluated in CNS receptor screens to delineate possible receptor combination strategies which may be appropriate for MDMA antagonism. PUBLIC HEALTH RELEVANCE: This research positively impacts human health by allowing for the identification and development of novel molecules which antagonize the effects of the designer drug "Ecstasy".