RT Journal Article SR Electronic T1 Discovery and Characterization of a G Protein-biased Agonist that Inhibits β-arrestin Recruitment to the D2 Dopamine Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.113.090563 DO 10.1124/mol.113.090563 A1 R. Benjamin Free A1 Lani S Chun A1 Amy E Moritz A1 Brittney Miller A1 Trevor B Doyle A1 Jennie L Conroy A1 Adrian Padron A1 Julie A Meade A1 Jingbo Xiao A1 Xin Hu A1 Andres E Dulcey A1 Yang Han A1 Lihua Duan A1 Steve Titus A1 Melanie Bryant-Genevier A1 Elena Barnaeva A1 Marc Ferrer A1 Jonathan A Javitch A1 Thijs Beuming A1 Lei Shi A1 Noel Southall A1 Juan J Marugan A1 David R Sibley YR 2014 UL http://molpharm.aspetjournals.org/content/early/2014/04/22/mol.113.090563.abstract AB A high-throughput screening campaign was conducted to interrogate a 380,000+ small molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and β-arrestin recruitment. While the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate β-arrestin recruitment. One such compound (MLS1547) is a highly efficacious agonist at D2 receptor-mediated G protein-linked signaling, but does not recruit β-arrestin, as demonstrated using two different assays. This compound does, however, antagonize dopamine-stimulated β-arrestin recruitment to the D2 receptor. In an effort to investigate the chemical scaffold of MLS1547 further, we characterized a set of 24 analogs of MLS1547 with respect to their ability to inhibit cAMP accumulation or stimulate β-arrestin recruitment. A number of the analogs were similar to MLS1547 in that they displayed agonist activity for inhibiting cAMP accumulation, but did not stimulate β-arrestin recruitment (i.e., they were highly biased). In contrast, other analogs displayed various degrees of G protein signaling bias. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure-activity relationship of the functionally-selective properties of this series of compounds. In summary, we have identified and characterized a novel G protein-biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties.