Allosteric Modulation of the Mu-Opioid Receptor

阿片类药物是高效的镇痛剂，但具有严重的靶向副作用。原则中 这些是导致目前阿片类药物危机的额外责任和呼吸抑制。这些影响 连同其他行动，包括便秘和恶心和呕吐，也降低了有效性， 阿片类药物在疼痛诊所因此，迫切需要开发新的镇痛剂或改善其临床应用。 现有的药物。吗啡和相关阿片类药物通过作用于正构神经元发挥作用， μ-阿片受体（莫尔）上的位点，即内源性阿片肽结合的位点。最近 我们对G蛋白偶联受体（GPCR）结构的了解的进展突出了 GPCR功能可能由结合在细胞上单独的变构位点的化合物控制。 受体。在这方面，作用于莫尔的正向别构调节剂（PAM）（MOR-PAM）已经被发现， 鉴定先前的实验表明，这些化合物起到变构调节正构位点的作用， 从而增加莫尔激动剂（包括内源性MOR激动剂）的结合亲和力、效力和/或最大反应 阿片肽，以探针依赖的方式。初步实验表明，莫尔-聚丙烯酰胺是 有效的抗伤害感受剂在小鼠体内通过增强内源性脑啡肽活性起作用， 从而避免了对阿片类药物如吗啡和羟考酮的需要。这种体内活性应保持 神经元信号传导的时间和空间特征，从而避免补偿机制 由慢性莫尔激活诱导。该应用通过使用结构生物学和 计算方法来确定莫尔上的变构结合位点，通过开发新的 变构探针，使我们能够更清楚地定义变构的机制，并进一步探索 初步发现，变构调节剂作为有效的疼痛缓解剂在体内工作。详细 了解莫尔的变构调节剂的作用将为MOR的机制提供新的信息 通过该方法可以控制莫尔功能，并且与高亲和力探针的鉴定一起，将为 莫尔调节剂作为新型镇痛剂的未来药物开发工作的方式， 莫尔镇痛效果无成瘾性和呼吸抑制。 相关性（参见说明）：

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):