Development of a preclinical candidate for the treatment of alcoholism

描述(申请人提供)：酗酒和与酒精有关的疾病给社会带来了巨大的压力。虽然有治疗方法可用，但在寻求治疗的不同人群中，没有一种方法是普遍有效的。我的研究重点是阐明两种增量阿片受体亚型(DOR1和DOR2)在酒精滥用障碍中的作用。它们同时影响酒精消费和焦虑的能力使这些DOR亚型有望成为治疗酒精中毒的潜在新药靶点。到目前为止，我发现DOR亚型在酒精消耗和焦虑方面具有独特的、有时是相反的影响。此外，我认为DOR‘S药理作用可能是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亚型独特药理背后的机制，并利用它开发可以更好地治疗酒精滥用障碍且副作用比目前可用的药物更少的新药。我研究的一个不可或缺的部分是解决慢性酒精暴露如何导致功能性DOR数量的增加。此外，我还设计了一种独特的方法来识别使用高通量体外试验选择性地与受体异构体相互作用的药物。我打算用酒精中毒的小鼠模型进一步测试本实验中确定的化合物，确定它们对酒精摄取、焦虑、奖励和酒精戒断的影响。我的最终目标是验证DOR亚型作为酒精滥用干预的新靶点，并确定最理想的DOR亚型选择性药物作为临床前先导的特性。 公共卫生相关性：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，但在寻求治疗的不同人群中，没有一种方法是普遍有效的。这项建议旨在研究新的药物靶点，并确定新的先导化合物，以更好地治疗酒精中毒，减少副作用。

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.