Toward Next Generation Analgesics:Activation Mechanism of the Nociceptin Receptor

 处方阿片类药物滥用影响240万美国人，每年造成557亿美元的社会负担。这些处方阿片类药物主要是β-阿片受体（莫尔）激动剂，不仅高度成瘾，而且其致命的副作用导致的过量死亡人数超过海洛因和可卡因的总和。因此，迫切需要进行研究以鉴定不存在与莫尔激动剂相关的滥用和严重副作用的可能性的镇痛剂。最近的研究表明，靶向伤害感受素受体（NOP）是一种有前途的替代途径，以缓解疼痛，而没有传统的MOR激活阿片类药物治疗的有害副作用。在非人灵长类动物中，特异性激活NOP诱导持久的、吗啡可比的镇痛，而不引起瘙痒、呼吸抑制或静脉内自我给药范例中的强化作用;从而消除了当前阿片类药物治疗的三种严重副作用。我们的目标是通过对NOP的深入结构研究，并利用我们对这一关键药物靶点的新发现的理解，开发不同NOP配体化学型作用的预测模型，来发展对NOP信号传导的机制性理解。这一目标将通过以下具体目标来实现：（1）确定和分析激活的NOP的三维分子结构;（2）描述NOP的组成型活性突变体的激活机制;（3）确定与效应片段复合的激动剂结合的NOP的结构。在整个项目中产生的结构和功能数据将在计算研究中结合和利用，以扩展我们对NOP激活的新理解，以识别新的NOP激活化学型。这一潜在的高影响力项目将为开发下一代镇痛药铺平道路，这些镇痛药缺乏与当前阿片类药物治疗相关的滥用倾向和严重副作用。

 DESCRIPTION (provided by applicant): Prescription opioid abuse affects 2.4 million Americans and poses a societal burden of $55.7 billion annually. These prescription opioids are primarily -opioid receptor (MOR) agonists, and are not only highly addictive but their deadly side effects have caused more overdose deaths than heroin and cocaine combined. Therefore, research to identify analgesics that lack the potential for abuse and severe side effects associated with MOR agonists are urgently needed. Recent studies indicate that targeting the nociceptin receptor (NOP) is a promising alternative route to relieving pain without the deleterious side effects of traditional MOR-activating opioid therapies. In non-human primates, specifically activating NOP induces long lasting, morphine-comparable analgesia without causing pruritus, respiratory depression, or reinforcing effects in an intravenous self-administration paradigm; thus eliminating three serious side-effects of current opioid therapies. Our goal is to develop a mechanistic understanding of NOP signaling through intensive structural studies of NOP and leveraging our newfound understanding of this critical drug target to develop a predictive model for the action of different NOP ligand chemotypes. This goal will be accomplished through the following specific aims: (1) Determine and analyze the three-dimensional molecular structure of activated NOP (2) Delineate the activation mechanism of constitutively active mutants of NOP and finally (3) Define the structure of agonist- bound NOP in complex with effector fragments. The structural and functional data generated throughout this project will be combined and leveraged in computational studies to extend our newfound understanding of NOP activation to the identification of new NOP-activating chemotypes. This potentially high-impact project would pave the way for the development of the next generation of analgesics that lack the abuse liability and serious side effects associated with current opioid therapies.