Nociceptin Receptor Agonists for Alcohol Use Disorders

治疗酒精使用障碍的药物治疗选择非常有限，目前只有三种药物被批准使用。此外，这些药物只有适度的效果，并没有被广泛使用，这可能是由于它们缺乏疗效。酒精成瘾的一个重要方面，往往是治疗不足是复发的可能性。因此，有效治疗酒精成瘾和复发需要新的、更广泛的药理学方法。Nociceptin/orphanin FQ （N/OFQ）是阿片样受体（ORL - 1）受体（也称为NOP）的内源性肽激动剂，可减少乙醇的奖励作用，并防止实验动物恢复乙醇寻求。然而，重要的是，N/OFQ被证明具有抗焦虑样和抗压力样活性，并作为CRF拮抗剂，在酒精成瘾的动物模型中逆转压力的行为影响。因此，NOP受体激动剂似乎是一个广泛的，有前途的策略，可能特别适合于治疗酒精成瘾的各个方面。该合同的目标是开发有效和选择性的NOP激动剂，特别优化其药物样适用性，并评估选定的优化NOP激动剂对乙醇诱导的条件位置偏好的影响。该项目的结果将是确定有效的NOP激动剂候选药物，适合进一步开发作为酒精成瘾和复发预防的潜在药物治疗。

There are very limited pharmacotherapy options for treatment of alcohol use disorders, with only three drugs currently approved for use. Further, these are only modestly effective and not widely prescribed, possibly due to their lack of efficacy. An Important facet of alcohol addiction that is often under-treated is the possibility of relapse. Effective treatment of alcohol addiction and relapse therefore, requires new, broader pharmacological approaches. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide agonist of the opioid receptor-like (ORL 1) receptor (also known as NOP) reduces the rewarding actions of ethanol and prevents reinstatement of ethanol seeking in laboratory animals. Importantly, however, N/OFQ is shown to have anti-anxiety-like and anti-stress-like activity, and functions as a CRF antagonist, to reverse behavioral effects of stress in animal models of alcohol addiction. Therefore, NOP receptor agonism appears to be a broad, promising strategy that may be particularly suitable for treating the various aspects of alcohol addiction. The goal of this contract Is to develop potent and selective NOP agonists, specifically optimized for their drug-like suitability, and to assess the effect of a selected optimized NOP agonist on ethanol-induced conditioned place preference. The outcome of this project will be the identification of efficacious NOP agonist drug candidates, suitable for further development as potential pharmacotherapy for alcohol addiction and relapse prevention.