Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists.

Journal Article (Journal Article)

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first β-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

Full Text

Duke Authors

Cited Authors

  • Chen, X; Sassano, MF; Zheng, L; Setola, V; Chen, M; Bai, X; Frye, SV; Wetsel, WC; Roth, BL; Jin, J

Published Date

  • August 23, 2012

Published In

Volume / Issue

  • 55 / 16

Start / End Page

  • 7141 - 7153

PubMed ID

  • 22845053

Pubmed Central ID

  • PMC3443605

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm300603y


  • eng

Conference Location

  • United States