Structure-activity relationship studies on Nantenine

描述（由申请人提供）：（“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（如热疗）有关，可能导致严重的器官损伤。MDMA具有神经毒性，在服用者中发现认知和心理缺陷。此外，有些人符合MDMA依赖的标准。目前对一种对抗MDMA过量和滥用的治疗剂的医疗需求尚未得到满足。阻断5-羟色胺5-HT2A和11A肾上腺素能受体在动物模型中已被证明可拮抗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，这是拮抗5-HT2A和11A肾上腺素能受体所必需的。我们将验证nantenine的结构修饰将产生新型5-HT2A拮抗剂和新型11A肾上腺素能受体拮抗剂的中心假设。为了验证这一假设，我们将进行结构-活性关系（SAR）研究，涉及三个具体目标。在第一个特定目的中，我们将研究南tenine A环上取代基的取代对拮抗目标受体的影响。对于第二个具体目标，将通过合成新的杂环衍生物来评估纳米汀的亚甲基二氧苯基环的药效相关性。在具体目标3中，将分析n取代基的重要性。选定的化合物将在啮齿动物中进行行为分析，以表征其作为潜在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. 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".