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: 7894966
• 负责人: Wayne Wesley Harding
• 金额: $ 19.71万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894966
• 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”）是一种流行的虐待药物，尤其是在人口中的青年中。 MDMA的使用与急性生理作用有关，其中高温的发展又可能导致严重的器官损害。 MDMA是神经毒性的，严重的认知，心理损害可能是由于滥用药物而造成的。此外，有证据表明，通过重复使用MDMA可以发展依赖性。目前，治疗剂的医疗需求未满足医疗需求，以应对MDMA的不良影响。该项目的目的是阐明我们的铅分子（+） - nantenine的结构特征，这是MDMA行为和生理效应的拮抗作用所必需的。我们将测试中心假设，即（+） - Nantenine的结构修饰将产生新型的载载mDMA拮抗剂。为了检验这一假设，我们将涉及两个特定目标的体内SAR研究。在第一个具体目的中，我们将研究取代基对Nantenine芳香环的替代对拮抗MDMA诱导在药物歧视测定法和高温测定中的作用的能力的影响。对于第二个特定目的，将类似地评估取代基在Nantenine N6位置的作用。将在中枢神经系统受体筛选中评估类似物，以描绘可能适合MDMA拮抗作用的受体组合策略。公共卫生相关性：这项研究通过允许鉴定和开发新型分子来对人类健康产生积极影响，从而拮抗设计师药物“摇头丸”的影响。

项目成果

Cytotoxicity of aporphines in human colon cancer cell lines HCT-116 and Caco-2: an SAR study.

• DOI: 10.1016/j.bmcl.2011.06.005
• 发表时间: 2011-08-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Ponnala, Shashikanth;Chaudhary, Sandeep;Gonzalez-Sarrias, Antonio;Seeram, Navindra P.;Harding, Wayne W.
• 通讯作者: Harding, Wayne W.