Discovery and Characterization of a G Protein-Biased Agonist That Inhibits beta-Arrestin Recruitment to the D2 Dopamine Receptor

作者：Free R Benjamin^*; Chun Lani S; Moritz Amy E; Miller Brittney N; Doyle Trevor B; Conroy Jennie L; Padron Adrian; Meade Julie A; Xiao Jingbo; Hu Xin; Dulcey Andres E; Han Yang; Duan Lihua; Titus Steve; Bryant Genevier Melanie; Barnaeva Elena; Ferrer Marc; Javitch Jonathan A; Beuming Thijs; Shi Lei; Southall Noel T; Marugan Juan J; Sibley David R

来源：Molecular Pharmacology, 2014, 86(1): 96-105.

DOI：10.1124/mol.113.090563

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 beta-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate beta-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 beta-arrestin as demonstrated using two different assays. This compound does, however, antagonize dopamine-stimulated beta-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 beta-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 beta-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.

• 出版日期2014-7
• 单位NIH