Design, synthesis and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the β2-adrenergic receptor

Publication date: Available online 15 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): 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 shown 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.

Graphical abstract

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