当前位置: X-MOL 学术Bioorg. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Design, synthesis, and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the β2-adrenergic receptor
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2018-03-15 , DOI: 10.1016/j.bmc.2018.03.023
Kaicheng Meng , Paul Shim , Qingtin Wang , Shuai Zhao , Ting Gu , Alem W. Kahsai , Seungkirl Ahn , Xin Chen

The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis and structure-activity relationships (SAR) of seven Cmpd-15 derivatives. Furthermore, we provide in a dose-response paradigm, the details of the effects of these derivatives in modulating agonist-induced β2AR activities (G-protein-mediated cAMP production and β-arrestin recruitment to the receptor) as well as the binding affinity of an orthosteric agonist in radio-ligand competition binding assay. Our results show that some modifications, including removal of the formamide group in the para-formamido phenylalanine region and bromine in the meta-bromobenzyl methylbenzamide region caused dramatic reduction in the functional activity of Cmpd-15. These SAR results provide valuable insights into the mechanism of action of the NAM Cmpd-15 as well as the basis for future development of more potent and selective modulators for the β2AR based on the chemical scaffold of Cmpd-15.



中文翻译:

设计,合成,和化合物-15的衍生物作为用于β负变构调节剂的功能评估2 -肾上腺素能受体

所述β 2 -肾上腺素能受体(β 2 AR),G蛋白偶联受体,是一个重要的治疗目标。我们最近描述CMPD-15,第一小分子负变构调节剂(NAM)为β 2 AR。本文中,我们详细报告了7种Cmpd-15衍生物的设计,合成和构效关系(SAR)。此外,我们提供一种在剂量-响应范例,它们的衍生物的效果的细节在调节激动剂诱导的β 2在放射性配体竞争结合试验中,AR活性(G蛋白介导的cAMP产生和β-arrestin募集到受体)以及正构激动剂的结合亲和力。我们的研究结果表明,一些修改,包括在除去甲酰胺基的-formamido苯丙氨酸区域和溴在-bromobenzyl甲基苯甲酰胺区域引起CMPD-15的功能活性显着降低。这些SAR结果提供了宝贵的见解NAM CMPD-15的作用机制以及为更有效和选择性调节剂的未来发展,为β的基础2基于CMPD-15的化学支架AR。

更新日期:2018-03-15
down
wechat
bug