@article {Free96, author = {R. Benjamin Free and Lani S. Chun and Amy E. Moritz and Brittney N. Miller and Trevor B. Doyle and Jennie L. Conroy and Adrian Padron and Julie A. Meade and Jingbo Xiao and Xin Hu and Andr{\'e}s E. Dulcey and Yang Han and Lihua Duan and Steve Titus and Melanie Bryant-Genevier and Elena Barnaeva and Marc Ferrer and Jonathan A. Javitch and Thijs Beuming and Lei Shi and Noel T. Southall and Juan J. Marugan and David R. Sibley}, title = {Discovery and Characterization of a G Protein{\textendash}Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor}, volume = {86}, number = {1}, pages = {96--105}, year = {2014}, doi = {10.1124/mol.113.090563}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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{\textendash}mediated G protein{\textendash}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{\textendash}biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/86/1/96}, eprint = {https://molpharm.aspetjournals.org/content/86/1/96.full.pdf}, journal = {Molecular Pharmacology} }