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: 8901731
• 负责人: Richard M. van Rijn
• 金额: $ 23.74万
• 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/8901731
• 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; 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; withdrawal-induced anxiety

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.

项目摘要/摘要 酗酒和与酒精相关的疾病给社会带来了巨大的压力。虽然有治疗方法可用，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 关于阐明两种三角洲阿片受体亚型(DOR1和DOR2)在酒精滥用障碍中的作用。 他们同时影响酒精消费和焦虑的能力使这些DOR亚型具有潜在的前景 治疗酒精中毒的新药物靶点。到目前为止，我已经发现DOR子类型具有唯一的AND 有时会对酒精消费和焦虑产生相反的影响。此外，我确定国防部的S 药理作用可能是DOR与MOR相互作用形成DOR-MOR异构体。我的 研究旨在确定DOR亚型和DOR亚型独特药理背后的机制 利用它开发新的药物，可以更好地治疗酒精滥用障碍，并且副作用比 目前可用的药物。我研究的一个不可或缺的部分是解决长期接触酒精的问题 导致功能性DOR的数量增加。此外，我还设计了一种独特的方法来 使用高通量体外试验鉴定选择性与受体异构体相互作用的药物。我打算 为了进一步测试本试验中确定的化合物，使用酒精中毒的小鼠模型，确定它们对 酒精摄入、焦虑、奖励和戒酒。我的最终目标是将DOR子类型验证为 酒精滥用干预的新靶点和确定最理想的DOR亚型的特性 选择性药物作为临床前的先导。

项目成果

Delta Opioid Pharmacology in Relation to Alcohol Behaviors.

• DOI: 10.1007/164_2016_30
• 发表时间: 2018
• 期刊: Handbook of experimental pharmacology
• 作者: Alongkronrusmee, Doungkamol;Chiang, Terrance;van Rijn, Richard M
• 通讯作者: van Rijn, Richard M

An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US.

对美国糖尿病、酒精和药物引起的神经病变、病因和治疗的综合视角。

• DOI: 10.2147/jpr.s125987
• 发表时间: 2017
• 期刊: Journal of pain research
• 影响因子: 2.7
• 作者: Zeng,Lily;Alongkronrusmee,Doungkamol;vanRijn,RichardM
• 通讯作者: vanRijn,RichardM

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice.

• DOI: 10.1016/j.drugalcdep.2016.08.017
• 发表时间: 2016-10-01
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: Alongkronrusmee D;Chiang T;van Rijn RM
• 通讯作者: van Rijn RM