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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Meng, K; Shim, P; Wang, Q; Zhao, S; Gu, T; Kahsai, AW; Ahn, S; Chen, X

Published Date

  • May 15, 2018

Published In

Volume / Issue

  • 26 / 9

Start / End Page

  • 2320 - 2330

PubMed ID

  • 29588128

Electronic International Standard Serial Number (EISSN)

  • 1464-3391

Digital Object Identifier (DOI)

  • 10.1016/j.bmc.2018.03.023


  • eng

Conference Location

  • England