Allosteric Modulation of the Mu-Opioid Receptor

Mu-阿片受体的变构调节

• 批准号: 10395590
• 负责人: John R. Traynor
• 金额: $ 69.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395590
• 关键词: Absence of pain sensation; Acute Pain; Affinity; Agonist; Allosteric Site; Amino Acids; Analgesics; Arrestins; Behavior; Behavioral; Binding; Binding Sites; Characteristics; Chemicals; Chemistry; Chronic; Clinical; Collaborations; Computing Methodologies; Constipation; Coupled; Coupling; Cryoelectron Microscopy; Cyclic AMP-Dependent Protein Kinases; Data; Development; Drug Design; Effectiveness; Enkephalins; Epidemic; Exposure to; Funding; Future; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GTP-Binding Proteins; Heterotrimeric GTP-Binding Proteins; In Vitro; Instruction; Knowledge; Ligands; Methionine Enkephalin; Modeling; Molecular; Morphine; Mus; Mutate; Nausea and Vomiting; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Peptide; Opioid Rotation; Opioid agonist; Oxycodone; Pain Clinics; Pathway interactions; Patients; Pharmaceutical Preparations; Property; Protein Kinase; Receptor Activation; Regulation; Relapse; Role; Side; Signal Transduction; Site; Structure; System; Testing; Translating; Transmembrane Domain; Ventilatory Depression; Work; addiction; addiction liability; antagonist; chronic pain; density; diverse data; drug development; endogenous opioids; experimental study; extracellular; gamma-Aminobutyric Acid; improved; in vivo; models and simulation; mu opioid receptors; neurotransmission; novel; opioid epidemic; pain relief; positive allosteric modulator; preservation; prevent; receptor; receptor binding; receptor function; recruit; respiratory; response; side effect; small molecule; structural biology; translational potential

Opioid drugs are highly effective analgesics but suffer from serious on-target side-effects. Principle among these are addition liability and respiratory depression that have led to the current opioid crisis. These effects together with other actions, including constipation and nausea and vomiting, also reduce the effectiveness of opioids in the pain clinic. Thus, there is a vital need to develop new analgesics or to improve the clinical profile of existing medications. Morphine and related opioids exert their effects by acting at the orthosteric site on the mu-opioid receptor (MOR), i.e. the site where the endogenous opioid peptides bind. Recent advances in our knowledge of the structure of G-protein coupled receptors (GPCRs) have highlighted the possibility that GPCR function may be controlled by compounds binding at a separate, allosteric, site on the receptors. In this regard positive allosteric modulators (PAMs) that act at MOR (MOR-PAMs) have been identified. Previous experiments show these compounds act to allosterically modulate the orthosteric site and so increase the binding affinity, potency and/or maximal response of MOR agonists, including endogenous opioid peptides, in a probe-dependent manner. Preliminary experiments demonstrate that MOR- PAMs are effective antinociceptive agents in vivo in the mouse and act by enhancing endogenous enkephalin activity, thus avoiding the need for opioid drugs such as morphine and oxycodone. This in vivo activity should preserve the temporal and spatial characteristics of neuronal signaling and so avoid compensatory mechanisms induced by chronic MOR activation. This application moves the field forward by using structural biology and computational methods to identify the allosteric binding site on MOR, aided by the development of new allosteric probes to allow us to more clearly define the mechanism of allosterism, and further exploration of preliminary findings that allosteric modulators work as effective pain relieving agents in vivo. Detailed understanding of the actions of allosteric modulators of MOR will provide new information on mechanisms by which MOR function may be controlled and, together with the identification of high affinity probes, will pave the way for future drug development efforts of MOR modulators as novel analgesics that safely harness the analgesic efficacy of MOR without addiction and respiratory depression. RELEVANCE (See instructions):

阿片类药物是高效的镇痛药，但存在严重的靶向副作用。其中原则 这些额外的责任和呼吸抑制导致了当前的阿片类药物危机。这些影响 与其他行为一起，包括便秘、恶心和呕吐，也会降低药物的有效性。 疼痛诊所中的阿片类药物。因此，迫切需要开发新的镇痛药或改进临床镇痛药。 现有药物的概况。吗啡和相关阿片类药物通过作用于正位神经发挥作用 mu-阿片受体 (MOR) 上的位点，即内源性阿片肽结合的位点。最近的 我们对 G 蛋白偶联受体 (GPCR) 结构认识的进步凸显了 GPCR 功能可能由结合在 GPCR 上单独的变构位点的化合物控制的可能性 受体。在这方面，作用于 MOR 的正变构调节剂 (PAM) (MOR-PAM) 已被 确定。先前的实验表明这些化合物可以变构调节正构位点并 因此增加 MOR 激动剂（包括内源性激动剂）的结合亲和力、效力和/或最大反应 阿片肽，以探针依赖性方式。初步实验表明 MOR-PAMs 小鼠体内有效的镇痛药，通过增强内源性脑啡肽活性起作用， 从而避免对吗啡和羟考酮等阿片类药物的需求。这种体内活性应该保持 神经元信号传导的时间和空间特征，从而避免补偿机制 由慢性 MOR 激活引起。该应用通过使用结构生物学和 借助新开发的计算方法来识别 MOR 上的变构结合位点 变构探针使我们能够更清楚地定义变构机制，并进一步探索 初步发现变构调节剂在体内可作为有效的疼痛缓解剂。详细的 了解 MOR 变构调节剂的作用将提供有关机制的新信息 通过它可以控制 MOR 功能，并与高亲和力探针的鉴定一起，将为 MOR 调节剂作为安全利用 MOR 调节剂的新型镇痛药的未来药物开发努力的方向 MOR的镇痛功效无成瘾性和呼吸抑制。 相关性（参见说明）：