Development of a preclinical candidate for the treatment of alcoholism

描述（由申请人提供）：酗酒和与酒精有关的疾病给社会带来了很大的压力。虽然治疗方法是可用的，但没有一种对寻求治疗的不同人群普遍有效。我的研究重点是阐明两种δ阿片受体亚型（DOR1和DOR2）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亚型成为治疗酒精中毒的潜在新药物靶点。到目前为止，我发现DOR亚型对乙醇消耗和焦虑有独特的，有时是相反的影响。此外，我确定DOR1的药理学可能是DOR与MOR相互作用形成DOR-MOR异构体的结果。我的研究旨在确定DOR亚型的独特药理学背后的机制，并利用它开发新的药物，可以更好地治疗酒精滥用障碍，并且比目前可用的药物副作用更少。我研究的一个组成部分是解决慢性酒精暴露如何导致功能性DORs数量增加。此外，我设计了一种独特的方法来识别药物选择性地与受体异构体相互作用，使用高通量体外试验。我打算用酒精中毒小鼠模型进一步测试在该试验中发现的化合物，确定它们对乙醇摄入、焦虑、奖励和乙醇戒断的影响。我的最终目标是验证dor亚型作为干预酒精滥用的新靶点，并确定最理想的dor亚型选择性药物的特性作为临床前先导。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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. This proposal sets out to investigate novel drug targets and identify new lead compounds to better treat alcoholism with reduced side effects.