Development of Nociceptin Receptor Agonists for Alcohol Use Disorders, Period of Performance 09/15/15 - 09/14/17; CPFF

用于治疗酒精使用障碍的痛敏肽受体激动剂的开发，实施期 2015 年 9 月 15 日 - 2017 年 9 月 14 日；

• 批准号: 9157939
• 负责人: NURULAIN ZAVERI
• 金额: $ 100万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-28 至 2017-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9157939
• 关键词: Affinity; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anxiety; Attenuated; Behavioral; Chronic; Clinical Trials; Computer Assisted; Development; Drug Design; Human; Laboratory Animals; Lead; Link; Modeling; Opioid Receptor; Peptides; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Relapse; Rewards; Stress; Structure; System; Withdrawal; Withdrawal Symptom; alcohol effect; alcohol seeking behavior; alcohol use disorder; anxiety-like behavior; base; craving; design; drug candidate; improved; mouse model; nociceptin; nociceptin receptor; novel; pre-clinical; preference; prevent; receptor; research clinical testing; small molecule

The long-term objective of this project is the discovery and development of novel high affinity and selective nociceptin opioid receptor (NOP) agonists that can be advanced into human clinical testing for alcoholism. While NOP agonists have not yet been clinically investigated for alcohol dependence, there is significant pharmacological evidence showing dysregulation of the nociceptin system by chronic alcohol intake linked to increased alcohol seeking and anxiety-like behavior. Indeed, nociceptin/orphanin FQ (N/OFQ), the endogenous peptide agonist of the NOP receptor reduces the rewarding actions of alcohol and prevents reinstatement of alcohol seeking in laboratory animals. Importantly, N/OFQ is shown to have anti-anxiety-like and anti-stress-like activity, attenuates alcohol withdrawal symptoms and can reverse the behavioral effects of stress in relapse models of alcohol addiction. These preclinical pharmacological findings strongly support the NOP receptor system as a promising target for treating alcohol addiction and suggest that small- molecule, drug-like NOP receptor agonists may be particularly suitable as a promising approach for treating the various aspects of alcohol addiction (craving, withdrawal and relapse). In Phase 1 of this project, novel classes of NOP agonists were designed, synthesized, and optimized for their potency and selectivity versus other opioid receptors using state-of- the-art medicinal chemistry approaches of rational drug design and computer-aided structure-based drug design. From this effort, a selected NOP agonist showed significant inhibition of alcohol preference in a mouse model of alcohol conditioned place preference, thus validating the pharmacological hypothesis that NOP agonists reduce the rewarding effects of alcohol. The Phase II project proposes to continue the lead optimization of novel NOP agonists with emphasis on improving their suitability as drug candidates for advancement into human clinical trials.

该项目的长期目的是发现和开发新型的高亲和力和选择性的nocceptin阿片受体（NOP）激动剂，可以将其推进到人类酒精中毒的临床测试中。尽管尚未对NOP激动剂的酒精依赖进行临床研究，但有大量的药理学证据表明，通过慢性酒精摄入量与寻求酒精和焦虑症的行为相关的慢性酒精摄入量失去了对NOCPTIN系统的调节。实际上，NOP受体的内源性肽激动剂会减少酒精的奖励作用，并防止在实验室动物中恢复饮酒。重要的是，N/OFQ显示出具有抗焦虑样和抗压力的活性，可减轻酒精戒断症状，​​并可以扭转压力在酗酒复发模型中的行为影响。这些临床前药理发现强烈支持NOP受体系统，这是治疗酒精成瘾的有希望的靶标，并表明小分子类似药物的NOP受体激动剂可能特别适合作为治疗酒精成瘾（渴望，戒断和复发）的各个方面的有前途的方法。在该项目的第1阶段中，使用最先进的药物设计和基于计算机辅助结构的药物设计设计，合成和优化了新型的NOP激动剂类别的效力和选择性与其他阿片类药物的受体相比，设计，合成和优化。从这项工作中，选定的NOP激动剂在酒精条件偏好的小鼠模型中表现出明显的抑制酒精偏爱，从而验证了NOP激动剂减少酒精奖励作用的药理学假设。第二阶段项目建议继续对新型NOP激动剂进行铅优化，重点是提高其作为候选毒品促进人类临床试验的适合性。