TY - JOUR T1 - Discovery and Characterization of a G Protein–Biased Agonist That Inhibits <em>β</em>-Arrestin Recruitment to the D2 Dopamine Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 96 LP - 105 DO - 10.1124/mol.113.090563 VL - 86 IS - 1 AU - R. Benjamin Free AU - Lani S. Chun AU - Amy E. Moritz AU - Brittney N. Miller AU - Trevor B. Doyle AU - Jennie L. Conroy AU - Adrian Padron AU - Julie A. Meade AU - Jingbo Xiao AU - Xin Hu AU - Andrés E. Dulcey AU - Yang Han AU - Lihua Duan AU - Steve Titus AU - Melanie Bryant-Genevier AU - Elena Barnaeva AU - Marc Ferrer AU - Jonathan A. Javitch AU - Thijs Beuming AU - Lei Shi AU - Noel T. Southall AU - Juan J. Marugan AU - David R. Sibley Y1 - 2014/07/01 UR - http://molpharm.aspetjournals.org/content/86/1/96.abstract N2 - 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. Although 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; 5-chloro-7-[(4-pyridin-2-ylpiperazin-1-yl)methyl]quinolin-8-ol) 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. ER -