非肽类神经降压素受体配体中的酰胺连接子在2型神经降压素受体的钙信号传导中起关键作用。
The amide linker in nonpeptide neurotensin receptor ligands plays a key role in calcium signaling at the neurotensin receptor type 2.
作者信息
Thomas James B, Giddings Angela M, Olepu Srinivas, Wiethe Robert W, Warner Keith R, Sarret Philippe, Longpre Jean-Michel, Runyon Scott P, Gilmour Brian P
机构信息
Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
Center for Drug Discovery, RTI International, PO Box 12194, Research Triangle Park, NC 27709, United States.
出版信息
Bioorg Med Chem Lett. 2015;25(10):2060-4. doi: 10.1016/j.bmcl.2015.03.083. Epub 2015 Apr 3.
Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesia in relevant preclinical models. The amide bond in nonpeptide NTS1 antagonists plays a central role in receptor recognition and molecular conformation. Using NTS2 FLIPR and binding assays, we found that it is also a key molecular structure for binding and calcium mobilization at NTS2. We found that reversed amides display a shift from agonist to antagonist activity and provided examples of the first competitive nonpeptide antagonists observed in the NTS2 FLIPR assay. These compounds will be valuable tools for determining the role of calcium signaling in vitro to NTS2 mediated analgesia.
通过G蛋白偶联受体2型神经降压素受体（NTS2）起作用的化合物在相关临床前模型中表现出镇痛作用。非肽NTS1拮抗剂中的酰胺键在受体识别和分子构象中起核心作用。通过NTS2荧光成像板读数器（FLIPR）和结合试验，我们发现它也是NTS2结合和钙动员的关键分子结构。我们发现反向酰胺显示出从激动剂活性到拮抗剂活性的转变，并提供了在NTS2 FLIPR试验中观察到的首个竞争性非肽拮抗剂的实例。这些化合物将成为确定钙信号在体外对NTS2介导的镇痛作用中所起作用的有价值工具。
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