Nociceptin Receptor Agonists for Alcohol Use Disorders

伤害感受肽受体激动剂治疗酒精使用障碍

• 批准号: 8758181
• 负责人: NURULAIN ZAVERI
• 金额: $ 29.72万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2014-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758181
• 关键词: Agonist; Alcohol dependence; Animal Model; Anxiety; Behavioral; Biological; Contracts; Development; Ethanol; Evaluation; Goals; In Vitro; Laboratory Animals; Lead; Ligands; Opioid Receptor; Outcome; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Relapse; Rewards; Stress; alcohol relapse; alcohol seeking behavior; alcohol use disorder; disorder later incidence prevention; drug candidate; effective therapy; in vivo; nociceptin; nociceptin receptor; novel; preference; prevent; receptor

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.

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，这些药物只是适度有效，并没有广泛开出处方，可能是因为它们缺乏疗效。酒精成瘾的一个重要方面往往得不到治疗，那就是复发的可能性。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。伤害素/孤啡肽FQ(N/OFQ)是阿片受体样受体(ORL-1)受体(也称为NOP)的内源性多肽激动剂，可减少乙醇的奖赏作用，并防止在实验动物中恢复对乙醇的寻求。然而，重要的是，N/OFQ被证明具有抗焦虑和抗应激样活性，并作为CRF拮抗剂，在酒精成瘾动物模型中逆转应激的行为影响。因此，NOP受体激动剂似乎是一种广泛的、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，特别针对其类药物适合性进行优化，并评估选定的优化NOP激动剂对乙醇诱导的条件性位置偏爱的影响。该项目的成果将是确定有效的NOP激动剂候选药物，适合进一步开发为潜在的酒精成瘾和预防复发的药物治疗。