Synthesis and Evaluation of Aporphines as MDMA Antagonists.

描述(由申请人提供)：摇头丸(摇头丸)是一种流行的滥用药物，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，其中之一是体温过高，进而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可能会发展成依赖。目前，对治疗药物的需求尚未得到满足，以对抗MDMA的不利影响。这个项目的目标是阐明我们的先导分子(+)-南藤氨酸的结构特征，这是拮抗MDMA的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的阿朴吗啡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高温实验中考察取代基对其对抗MDMA诱导效应的能力的影响。对于第二个特定目的，将类似地评估纳米烯N6位上的取代基的作用。类似物将在中枢神经系统受体筛选中进行评估，以描述可能适用于MDMA拮抗的受体组合策略。与公共健康相关：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”的效果，从而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".