Structure-activity relationship studies on Nantenine

Nantenine的构效关系研究

• 批准号: 8459367
• 负责人: Wayne Wesley Harding
• 金额: $ 29.53万
• 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/8459367
• 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”）是一种流行的虐待药物，尤其是在人口中的青年中。 MDMA的使用与急性生理效应（例如，高温）有关，这可能导致严重的器官损害。 MDMA是神经毒性的，认知和心理缺陷已在该药物的消费者中注意到。此外，有些人符合依赖MDMA的标准。目前，对治疗剂的医疗需求未满足，以对抗MDMA过量和滥用。在动物模型中，已证明了5-羟色胺5-HT2A和11A肾上腺素受体的封锁可拮抗MDMA诱导的行为和生理作用。该项目的目的是阐明5-HT2A和11A肾上腺素能受体所必需的铅分子Nantenine的结构特征。我们将检验以下中心假设，即非坦氨酸的结构修饰将产生新颖的5-HT2A拮抗剂和新型的11A肾上腺素受体拮抗剂。为了检验这一假设，我们将涉及三个特定目标的结构活性关系（SAR）研究。在第一个特定目的中，我们将检查取代基对靶向受体的替换对拮抗靶向受体的影响。对于第二个特定目的，将通过合成新型的杂环衍生物来评估非兰氨酸甲基二苯基环的药物相关性。在特定的目标3中，将分析N-核能组的重要性。选定的化合物将推进啮齿动物的行为测定，以将其药理特征表征为潜在的MDMA拮抗剂。