2. Academic Validation
  3. Discovery and characterization of a G protein-biased agonist that inhibits β-arrestin recruitment to the D2 dopamine receptor

Discovery and characterization of a G protein-biased agonist that inhibits β-arrestin recruitment to the D2 dopamine receptor

  • Mol Pharmacol. 2014 Jul;86(1):96-105. doi: 10.1124/mol.113.090563.
R Benjamin Free 1,  Lani S Chun 2,  Amy E Moritz 2,  Brittney N Miller 2,  Trevor B Doyle 2,  Jennie L Conroy 2,  Adrian Padron 2,  Julie A Meade 2,  Jingbo Xiao 2,  Xin Hu 2,  Andrés E Dulcey 2,  Yang Han 2,  Lihua Duan 2,  Steve Titus 2,  Melanie Bryant-Genevier 2,  Elena Barnaeva 2,  Marc Ferrer 2,  Jonathan A Javitch 2,  Thijs Beuming 2,  Lei Shi 2,  Noel T Southall 2,  Juan J Marugan 2,  David R Sibley 2
Affiliations

Affiliations

  • 1 Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., L.S.C., A.E.M., B.N.M., T.B.D., J.L.C., A.P., J.A.M., D.R.S.); National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland (J.X., X.H., A.E.D., S.T., M.B.-G., E.B., M.F., N.T.S., J.J.M.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (Y.H., L.D., J.A.J.); Schrödinger Inc., New York, New York (T.B.); and Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (L.S.) [email protected].
  • 2 Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., L.S.C., A.E.M., B.N.M., T.B.D., J.L.C., A.P., J.A.M., D.R.S.); National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland (J.X., X.H., A.E.D., S.T., M.B.-G., E.B., M.F., N.T.S., J.J.M.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (Y.H., L.D., J.A.J.); Schrödinger Inc., New York, New York (T.B.); and Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (L.S.).
PMID: 24755247 DOI: 10.1124/mol.113.090563
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-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.

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