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，特别是在青年人中。使用二亚甲基双氧安非他明会产生急性生理效应，其中包括体温过高，这反过来又可能导致严重的器官损伤。二亚甲基双氧安非他明具有神经毒性，滥用这种药物可造成严重的认知和心理损害。此外，有证据表明，重复使用摇头丸会产生依赖性。目前，治疗剂对抗MDMA不良反应的医学需求尚未得到满足。本项目的目标是阐明我们的先导分子（+）-nantenine的结构特征，这是必需的MDMA的行为和生理效应的拮抗作用。我们将测试的中心假设，（+）-nantenine的结构修饰将产生新的阿朴啡MDMA拮抗剂。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。在第一个具体的目标，我们将检查取代基上的芳香环的nantenine对他们的能力，拮抗MDMA诱导的药物歧视测定和热疗测定的影响。对于第二个具体目标，将类似地评估南天宁的N6位上的取代基的作用。将在CNS受体筛选中评价类似物，以描述可能适用于MDMA拮抗作用的可能受体组合策略。公共卫生相关性：这项研究对人类健康产生了积极的影响，因为它允许识别和开发新的分子，这些分子可以拮抗设计药物“Eclampsia”的作用。

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".