Synthesis and Evaluation of Aporphines as MDMA Antagonists.

作为 MDMA 拮抗剂的阿朴啡的合成和评价。

• 批准号: 7738621
• 负责人: Wayne Wesley Harding
• 金额: $ 20.97万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738621
• 关键词: Acute; Adrenergic Receptor; Adverse effects; Affinity; Alkaloids; Animal Experiments; Animal Model; Aporphines; Behavioral; Biological; Biological Assay; Cessation of life; Cognition; Cognitive; Complex; Dependence; Designer Drugs; Development; Drug Design; Drug abuse; Drug usage; Evaluation; Failure; Fever; Goals; HTR2A gene; Head; Health; Human; Impairment; In Vitro; Individual; Intoxication; Knowledge; Lead; Medical; Modification; Moods; Mus; Organ; Pharmaceutical Preparations; Physiological; Play; Population; Positioning Attribute; Principal Investigator; Property; Psychopharmacology; Psychotropic Drugs; Research; Rodent Model; Role; Serotonin Receptor 5-HT2A; Stimulus; Structure-Activity Relationship; Surveys; System; Talents; Testing; Therapeutic; Therapeutic Agents; Time; Work; Youth; aged; analog; body system; club drug; combat; drug discrimination; drug of abuse; ecstasy; ecstasy drug dependence; experience; in vivo; neurotoxic; neurotoxicity; novel; prevent; psychologic; public health relevance; receptor; response

DESCRIPTION (provided by applicant): MDMA ("Ecstasy") is a popular drug of abuse especially among youth in the population. Use of MDMA is associated with acute physiological effects among which is the development of hyperthermia, which in turn may lead to serious organ damage. MDMA is neurotoxic and severe cognitive and psychological damage can result from abuse of the drug. Furthermore, there is evidence that dependence can develop with repeated use of MDMA. There is an unmet medical need for a therapeutic agent to combat the adverse effects of MDMA at this time. The goal of this project is to elucidate structural features of our lead molecule (+)-nantenine, which are required for antagonism of behavioral and physiological effects of MDMA. We will test the central hypothesis that structural modification of (+)-nantenine will yield novel aporphine MDMA antagonists. To test this hypothesis we will engage an in vivo SAR study involving two specific aims . In the first specific aim we will examine the effects of replacement of substituents on the aromatic rings of nantenine on their ability to antagonize MDMA-induced effects in a drug discrimination assay and hyperthermia assay. For the second specific aim the role of substituents at the N6 position of nantenine will be similarly evaluated. Analogs will be evaluated in CNS receptor screens to delineate possible receptor combination strategies which may be appropriate for MDMA antagonism. PUBLIC HEALTH RELEVANCE: This research positively impacts human health by allowing for the identification and development of novel molecules which antagonize the effects of the designer drug "Ecstasy".

描述（由申请人提供）：MDMA（“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有关，其中包括体温过高，进而可能导致严重的器官损伤。 MDMA 具有神经毒性，滥用该药物可能会导致严重的认知和心理损害。此外，有证据表明重复使用 MDMA 会产生依赖性。目前对治疗药物来对抗 MDMA 的副作用的医疗需求尚未得到满足。该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 MDMA 的行为和生理效应所必需的。我们将测试 (+)-nantenine 的结构修饰将产生新型阿朴啡 MDMA 拮抗剂的中心假设。为了检验这一假设，我们将进行一项涉及两个特定目标的体内 SAR 研究。在第一个具体目标中，我们将研究南藤宁芳环上取代基的取代对其在药物辨别试验和热疗试验中拮抗 MDMA 诱导效应的能力的影响。对于第二个具体目标，将对南藤宁的 N6 位取代基的作用进行类似的评估。将在 CNS 受体筛选中评估类似物，以描绘可能适合 MDMA 拮抗作用的可能受体组合策略。公共健康相关性：这项研究通过识别和开发能够拮抗设计药物“摇头丸”作用的新型分子，对人类健康产生积极影响。