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

该项目的长期目标是发现和开发新型高亲和力和选择性的痛敏素阿片受体（NOP）激动剂，可用于人类酒精中毒的临床试验。虽然NOP激动剂尚未进行酒精依赖的临床研究，但有重要的药理学证据表明，慢性酒精摄入导致的伤害感受素系统失调与酒精寻求和焦虑样行为增加有关。事实上，伤害感受素/神经肽FQ（N/OFQ），NOP受体的内源性肽激动剂，减少了酒精的奖励作用，并防止实验室动物酒精寻求的恢复。重要的是，N/OFQ被证明具有抗焦虑样和抗压力样活性，减轻酒精戒断症状，并可以逆转酒精成瘾复发模型中压力的行为影响。这些临床前药理学发现强烈支持NOP受体系统作为治疗酒精成瘾的有希望的靶标，并表明小分子药物样NOP受体激动剂可能特别适合作为治疗酒精成瘾的各个方面（渴望、戒断和复发）的有希望的方法。在该项目的第1阶段，使用合理药物设计和计算机辅助基于结构的药物设计的最新药物化学方法，设计、合成并优化了新型NOP激动剂相对于其他阿片受体的效力和选择性。从这一努力中，选择的NOP激动剂在酒精条件性位置偏好的小鼠模型中显示出对酒精偏好的显著抑制，从而验证了NOP激动剂降低酒精的奖励作用的药理学假设。II期项目建议继续对新型NOP激动剂进行先导优化，重点是提高其作为候选药物进入人体临床试验的适用性。

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.