Allosteric Modulation of the Mu-Opioid Receptor

阿片类药物是高效的止痛药，但存在严重的靶向副作用。其中的原则 这些是额外的责任和呼吸抑制，导致了目前的阿片类药物危机。这些影响 与便秘、恶心和呕吐等其他行为一起，也会降低 疼痛诊所里的阿片类药物。因此，迫切需要开发新的止痛药或改善临床 现有药物简介。吗啡和相关阿片类药物通过作用于正构体而发挥作用 Mu-阿片受体(MOR)上的位点，即内源性阿片肽结合的部位。近期 我们对G蛋白偶联受体(GPCRs)结构的了解进展突显了 GPCR功能可能由结合在上一个单独的变构位点的化合物控制 感受器。在这方面，作用于MOR的正变构调节剂(PAM)一直是 已确认身份。以前的实验表明，这些化合物可以通过变构来调节正构位和 从而增加MOR激动剂的结合亲和力、效力和/或最大反应，包括内源性 阿片肽，以探针依赖的方式。初步实验表明，MOR-PAM是 小鼠体内有效的抗伤害性药物，并通过增强内源性脑啡肽活性发挥作用， 从而避免了吗啡和羟考酮等阿片类药物的需要。这种体内活动应该能保持 神经元信号的时间和空间特征，从而避免代偿机制 慢性MOR激活所致。该应用程序通过使用结构生物学和 MOR上变构结合位置的计算方法，辅助新的发展 变构探针使我们能够更清楚地定义变构作用的机制，并进一步探索 初步发现变构调节剂在体内作为有效的止痛剂发挥作用。详细 了解MOR的变构调节剂的作用将为机制提供新的信息 通过它可以控制MOR功能，并与高亲和力探针的鉴定一起铺平 作为新型镇痛剂的MOR调节剂未来药物开发的途径是安全地利用 无成瘾和呼吸抑制的吗啡的止痛效果。 相关性(请参阅说明)：

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):