Toward Next Generation Analgesics:Activation Mechanism of the Nociceptin Receptor

 描述(申请人提供)：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-阿片受体(MOR)激动剂，不仅高度上瘾，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，迫切需要研究确定与MOR激动剂相关的止痛药缺乏滥用和严重副作用的可能性。最近的研究表明，靶向伤害素受体(NOP)是一种有希望的替代方法，可以缓解疼痛，而不会产生传统的吗啡激活阿片类药物的不良副作用。在非人类灵长类动物中，特异性地激活NOP可以诱导持久的、与吗啡相当的止痛，而不会引起瘙痒、呼吸抑制或静脉注射自我给药范例中的强化效应；从而消除了目前阿片类药物治疗的三个严重副作用。我们的目标是通过对NOP的深入结构研究来发展对NOP信号的机制理解，并利用我们对这一关键药物靶点的新发现来开发不同NOP配体化学类型的作用预测模型。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的结构性活性突变体的激活机制；(3)确定与激动剂结合的NOP的结构与效应片段的复合体。整个项目产生的结构和功能数据将被结合并在计算研究中利用，以扩展我们对NOP激活的新理解，以识别新的NOP激活化学类型。这一可能产生重大影响的项目将为下一代止痛药的开发铺平道路，这种止痛药没有与目前的阿片类药物疗法相关的滥用责任和严重副作用。

 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.