Development of a preclinical candidate for the treatment of alcoholism

开发治疗酒精中毒的临床前候选药物

• 批准号: 8729460
• 负责人: Richard M. van Rijn
• 金额: $ 24.15万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729460
• 关键词: Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anti-Anxiety Agents; Anxiety; Binding; Biological Assay; Chronic; Development; Disease; Drug Interactions; Drug Targeting; Drug usage; Ethanol; FDA approved; G-Protein-Coupled Receptors; Goals; Hyperalgesia; In Vitro; Individual; Intervention; Lead; Left; Ligands; Methods; Molecular; Mus; Naltrexone; Nature; Opioid; Opioid Receptor; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population Heterogeneity; Property; Relapse; Research; Rewards; Role; Societies; Stimulus; Testing; Therapeutic; Time; Withdrawal; abstracting; alcohol behavior; alcohol exposure; alcoholism therapy; clinically relevant; delta opioid receptor; design; drinking; drinking behavior; drug efficacy; in vitro Assay; in vivo; mouse model; novel; pre-clinical; preference; radioligand; receptor; response; screening

Project Summary/Abstract Alcoholism and alcohol related illnesses put a large strain on society. While therapeutics are available, none are universally effective among the diverse population of treatment seeking individuals. My research is focused on elucidating the role of two delta opioid receptor subtypes (DOR1 and DOR2) in alcohol abuse disorders. Their ability to affect both ethanol consumption and anxiety make these DOR subtypes promising potential novel drug targets to treat alcoholism. So far I have discovered that the DOR subtypes have unique and sometimes opposing effects on ethanol consumption and anxiety. Moreover, I determined that the DOR1's pharmacology may result from an interaction of the DOR with the MOR forming a DOR-MOR heteromer. My research is designed to determine the mechanism behind the unique pharmacology of the DOR subtypes and exploit it to develop novel drugs that can treat alcohol abuse disorders better and with fewer side effects than the currently available medication. One integral part of my research is resolving how chronic ethanol exposure results in an increase in the number of functional DORs. Additionally, I have designed a unique method to identify drugs that selectively interact with receptor heteromers using a high throughput in vitro assay. I intend to further test compounds identified in this assay using mice models of alcoholism, determining their effects on ethanol intake, anxiety, reward and ethanol withdrawal. My ultimate goal is to validate a DOR-subtype as a new target for intervention in alcohol abuse and determine the properties of the most ideal DOR-subtype selective drug as a preclinical lead.

项目总结/摘要 酗酒和与酒精有关的疾病给社会带来了巨大的压力。虽然有治疗方法，但没有 在寻求治疗的不同人群中普遍有效。我的研究重点是 阐明两种δ阿片受体亚型（DOR 1和DOR 2）在酒精滥用障碍中的作用。 它们影响乙醇消耗和焦虑的能力使这些DOR亚型具有很大的潜力 治疗酒精中毒的新药物靶点。到目前为止，我发现DOR亚型具有独特的， 有时会对酒精消耗和焦虑产生相反的影响。此外，我确定DOR 1的 药理学上的差异可能是由于DOR与莫尔相互作用形成DOR-莫尔异聚体。我 研究旨在确定DOR亚型独特药理学背后的机制， 利用它来开发新的药物，可以更好地治疗酒精滥用障碍，副作用更少， 目前可用的药物。我的研究的一个组成部分是解决慢性酒精暴露 导致功能DOR数量的增加。此外，我还设计了一种独特的方法， 使用高通量体外分析鉴定与受体异聚体选择性相互作用的药物。我打算 为了使用小鼠酒精中毒模型进一步测试在该测定中鉴定的化合物， 乙醇摄入量、焦虑、奖励和乙醇戒断。我的最终目标是验证DOR子类型作为 酒精滥用干预的新目标，并确定最理想的DOR亚型的属性 选择性药物作为临床前先导药物。