Structure-activity relationship studies on Nantenine

描述(申请人提供)：(“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(如体温过高)有关，可能导致严重的器官损害。MDMA具有神经毒性，已注意到该药物的消费者存在认知和心理缺陷。此外，有些人符合依赖摇头丸的标准。目前，治疗药物的需求尚未得到满足，需要一种治疗药物来对抗MDMA过量和滥用。在动物模型中，阻断5-羟色胺5-HT2A和11A肾上腺素能受体已被证明可以拮抗MDMA引起的一系列行为和生理效应。这个项目的目标是阐明我们的先导分子南藤碱的结构特征，这些结构特征是拮抗5-HT2A和11A肾上腺素能受体所必需的。我们将检验中心假设，即对Nantenine的结构修饰将产生新的5-HT2A拮抗剂和新的11A肾上腺素能受体拮抗剂。为了验证这一假设，我们将进行一项涉及三个具体目标的结构-活性关系(SAR)研究。在第一个特定的目标中，我们将考察取代南藤碱A环上的取代基对靶向受体的拮抗作用。对于第二个特定目的，将通过合成新的杂环衍生物来评价南藤宁的亚甲二氧基苯环的药效相关性。在具体目标3中，将分析N-取代基的重要性。选定的化合物将被推进到啮齿动物的行为测试中，以表征它们作为潜在的MDMA拮抗剂的药理学特征。 与公共健康相关：这项研究通过允许识别和开发具有潜在拮抗设计药物“摇头丸”效果的新分子，对人类健康产生积极影响。

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. PUBLIC HEALTH RELEVANCE: This research positively impacts human health by allowing for the identification and development of novel molecules with the potential to antagonize the effects of the designer drug "Ecstasy".