Discovery, Synthesis, and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor
Discovery, Synthesis, and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor
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DOI：
10.1021/acs.jmedchem.5b00007
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发表时间：
2015-05-28
影响因子：
7.3
通讯作者：
Alt, Andrew
中科院分区：
文献类型：
--
作者：
Burford, Neil T.;Livingston, Kathryn E.;Alt, Andrew
G蛋白偶联受体（GPCR）的变构调节剂与结合受体的正构位点的激动剂或拮抗剂相比具有许多潜在的优点。这些包括受体选择性的潜力、体内信号传导的时间和空间保真度的维持、可防止过量问题的变构协同性的天花板效应以及通过差异调节不同信号传导途径产生偏倚。在这里，我们描述了δ阿片受体选择性正变构调节剂（δ PAMs）的发现，合成和分子药理学。如通过受体结合、G蛋白活化、β-抑制蛋白募集、腺苷酸环化酶抑制和细胞外信号调节激酶（ERK）活化所测量的，这些Δ PAM增加正构激动剂亮脑啡肽、SNC 80和TAN 67的亲和力和/或功效。因此，这些化合物是探测δ受体的分子药理学和探索δ PAM在诸如慢性疼痛和抑郁症的疾病中的治疗潜力的有用的药理学工具。
Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of delta-opioid receptor-selective positive allosteric modulators (delta PAMs). These delta PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, beta-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the delta receptor and to explore the therapeutic potential of delta PAMs in diseases such as chronic pain and depression.