Structure-activity relationship studies on Nantenine

描述（由申请人提供）：（“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（如体温过高），可能导致严重的器官损伤。MDMA具有神经毒性，在该药物的消费者中发现了认知和心理缺陷。此外，有些人符合对亚甲二氧基甲基安非他明依赖的标准。目前，治疗MDMA过量和滥用的治疗剂的医疗需求尚未得到满足。在动物模型中，5-羟色胺5-HT 2A和11 A肾上腺素能受体的阻断剂可拮抗MDMA诱导的一系列行为和生理效应。本项目的目标是阐明我们的先导分子nantenine的结构特征，所需的拮抗5-HT 2A和11 A肾上腺素能受体。我们将测试的中心假设，南替宁的结构修饰将产生新的5-HT 2A拮抗剂和新的11 A肾上腺素受体拮抗剂。为了验证这一假设，我们将进行一项涉及三个具体目标的构效关系（SAR）研究。在第一个具体目标中，我们将研究nantenine A环上取代基的替换对靶向受体的拮抗作用。对于第二个具体目标，将通过合成新的杂环衍生物来评估南替宁的亚甲基二氧基苯基环的药效学相关性。在具体目标3中，将分析N-取代基的重要性。选定的化合物将先进的啮齿类动物的行为测定，以表征其作为潜在的MDMA拮抗剂的药理学特征。

DESCRIPTION (provided by applicant): ("Ecstasy") is a popular drug of abuse especially among youth in the population. Use of MDMA is associated with acute physiological effects (e.g. hyperthermia) which may lead to serious organ damage. MDMA is neurotoxic and cognitive and psychological deficits have been noted in consumers of the drug. Furthermore, some individuals meet the criteria for dependence on MDMA. There is currently an unmet medical need for a therapeutic agent to combat MDMA overdose and abuse. Blockade of serotonin 5-HT2A and 11A adrenergic receptors have been shown to antagonize a range of MDMA- induced behavioral and physiological effects in animal models. The goal of this project is to elucidate structural features of our lead molecule nantenine that are required for antagonism of 5-HT2A and 11A adrenergic receptors. We will test the central hypothesis that structural modifications of nantenine will yield novel 5-HT2A antagonists and novel 11A adrenoceptor antagonists. To test this hypothesis we will engage a structure-activity relationship (SAR) study involving three specific aims. In the first specific aim, we will examine the effects of replacement of substituents on ring A of nantenine on antagonizing the targeted receptors. For the second specific aim, the pharmacophoric relevance of the methylenedioxyphenyl ring of nantenine will be evaluated through the synthesis of novel heterocyclic derivatives. In specific aim 3, the importance of the N-substituent group will be analyzed. Selected compounds will be advanced to behavioral assays in rodents in order to characterize their pharmacological profiles as potential MDMA antagonists.