3-Amino-5-(4-benzylphenyl)thieno[2,3-d]pyrimidin-4-one, 3-Amino-5-[4-(phenylmethyl)phenyl]thieno[2,3-d]pyrimidin-4(3H)-one (Barbadin)

selective ß-arrestin/ß2-adaptin inhibitor

Chemical Formula: C19H15N3OS

Molecular Weight: 333.4

OTAVAchemicals Catalogue Number: 0129720278

CAS Registry Number: 356568-70-2

Purity: 97% (HPLC)

Ref.: Beautrait, A et al. A new inhibitor of the ß-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling. Nat. Commun. 8, 15054

Abstract: In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, ß-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of ß-arrestin recruitment to the receptor and ß-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between ß-arrestin and the ß2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/ß-arrestin complexes. This selective ß-arrestin/ß2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical ß2-adrenergic (ß2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect ß-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and ß2AR, supporting the concept of ß-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

DOI: 10.1038/ncomms15054 (2017)