Structure-activity relationship studies on Nantenine

Nantenine的构效关系研究

• 批准号: 8607557
• 负责人: Wayne Wesley Harding
• 金额: $ 30.6万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607557
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Adverse effects; Affect; Affinity; Alkaloids; Amphetamines; Animal Model; Animals; Aporphines; Behavioral; Behavioral Assay; Cognition; Cognitive; Data; Dependence; Designer Drugs; Development; Drug usage; Elements; Failure; Goals; HTR2A gene; Head; Health; Human; Hyperthermia; Impairment; Individual; Intoxication; Lead; Leadership; Libraries; Medical; Methamphetamine; Modification; Moods; Organ; Pharmaceutical Preparations; Physiological; Population; Positioning Attribute; Prazosin; Preclinical Drug Evaluation; Property; Psychotropic Drugs; Research; Rodent; Screening Result; Serotonin; Structure-Activity Relationship; Surveys; Testing; Therapeutic Agents; Time; United States National Institutes of Health; Youth; adrenergic; aged; analog; base; body system; career; club drug; combat; design; drug of abuse; ecstasy; ecstasy drug dependence; ecstasy overdose; in vivo; insight; meetings; methyl group; neurotoxic; neurotoxicity; novel; overdose death; programs; psychologic; receptor; receptor binding; response; screening

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.

描述（由申请人提供）：（“摇头丸”）是一种流行的滥用药物，尤其是在年轻人中。 MDMA 的使用与急性生理效应（例如高热）有关，可能导致严重的器官损伤。 MDMA 具有神经毒性，该药物的使用者会出现认知和心理缺陷。此外，有些人符合 MDMA 依赖标准。目前，针对 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，阻断血清素 5-HT2A 和 11A 肾上腺素能受体已被证明可以拮抗一系列 MDMA 诱导的行为和生理效应。该项目的目标是阐明我们的先导分子南藤宁的结构特征，这些特征是拮抗 5-HT2A 和 11A 肾上腺素能受体所需的。我们将测试核心假设，即南藤宁的结构修饰将产生新型 5-HT2A 拮抗剂和新型 11A 肾上腺素受体拮抗剂。为了检验这一假设，我们将进行涉及三个具体目标的结构-活动关系（SAR）研究。在第一个具体目标中，我们将研究南藤宁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，将通过合成新型杂环衍生物来评估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。选定的化合物将在啮齿类动物中进行行为测定，以表征其作为潜在 MDMA 拮抗剂的药理学特征。