Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor
Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor
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DOI：
10.1073/pnas.1300393110
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发表时间：
2013-06-25
影响因子：
11.1
通讯作者：
Alt, Andrew
中科院分区：
文献类型：
--
作者：
Burford, Neil T.;Clark, Mary J.;Alt, Andrew
由于激动剂（如吗啡）用于治疗慢性疼痛的治疗价值，mu-阿片受体是研究最多的G蛋白偶联受体之一。然而，这些药物有明显的副作用，如呼吸抑制、便秘、异常性疼痛、耐受性和依赖性，以及滥用的可能性。努力微调疼痛控制，同时减轻药物的生理和心理副作用，导致了多种结构多样的阿片受体激动剂配体的发展，以及靶向kappa（-）和delta-阿片受体的化合物。近年来，一些G蛋白偶联受体的变构配体的鉴定为获得受体亚型选择性提供了突破，可以减少潜在药物的总体副作用。然而，正变构调节剂（positive allosteric modulators, pam）也具有特定的优势，即当正构激动剂占据受体时，仅调节受体的活性，从而在体内维持对受体信号的时空控制。变构调节剂的第二个优势可能会在阿片受体研究方面取得突破，并且与正构阿片受体激动剂相比，可能会产生副作用改善或耐受性和依赖性减少的药物。在这里，我们描述了使用β -抑制蛋白招募试验从高通量筛选中鉴定出的mu-阿片受体pam和沉默变构调节剂的发现和表征。
mu-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the mu-opioid receptor, as well as compounds that target kappa(-) and delta-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators ( PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of mu-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a beta-arrestin-recruitment assay.