RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 96
OP 105
DO 10.1124/mol.113.090563
VO 86
IS 1
A1 Free, R. Benjamin
A1 Chun, Lani S.
A1 Moritz, Amy E.
A1 Miller, Brittney N.
A1 Doyle, Trevor B.
A1 Conroy, Jennie L.
A1 Padron, Adrian
A1 Meade, Julie A.
A1 Xiao, Jingbo
A1 Hu, Xin
A1 Dulcey, Andrés E.
A1 Han, Yang
A1 Duan, Lihua
A1 Titus, Steve
A1 Bryant-Genevier, Melanie
A1 Barnaeva, Elena
A1 Ferrer, Marc
A1 Javitch, Jonathan A.
A1 Beuming, Thijs
A1 Shi, Lei
A1 Southall, Noel T.
A1 Marugan, Juan J.
A1 Sibley, David R.
YR 2014
UL http://molpharm.aspetjournals.org/content/86/1/96.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. 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.