Burford Neil T, Livingston Kathryn E, Canals Meritxell, Ryan Molly R, Budenholzer Lauren M L, Han Ying, Shang Yi, Herbst John J, O'Connell Jonathan, Banks Martyn, Zhang Litao, Filizola Marta, Bassoni Daniel L, Wehrman Tom S, Christopoulos Arthur, Traynor John R, Gerritz Samuel W, Alt Andrew
†Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
‡Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2015 May 28;58(10):4220-9. doi: 10.1021/acs.jmedchem.5b00007. Epub 2015 May 7.
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 δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-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 δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.
与结合于受体正构位点的激动剂或拮抗剂相比，G蛋白偶联受体（GPCRs）的变构调节剂具有许多潜在优势。这些优势包括受体选择性的潜力、体内信号传导时间和空间保真度的维持、变构协同作用的天花板效应（这可能防止过量问题）以及通过差异调节不同信号通路产生偏向性。在此，我们描述了δ-阿片受体选择性正变构调节剂（δ PAMs）的发现、合成及分子药理学。这些δ PAMs增加了正构激动剂亮氨酸脑啡肽、SNC80和TAN67的亲和力和/或效力，这通过受体结合、G蛋白激活、β- arrestin募集、腺苷酸环化酶抑制以及细胞外信号调节激酶（ERK）激活来衡量。因此，这些化合物是用于探究δ受体分子药理学以及探索δ PAMs在慢性疼痛和抑郁症等疾病中的治疗潜力的有用药理学工具。
