Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors

ACS Chem Neurosci. 2015 Jun 17;6(6):911-9. doi: 10.1021/acschemneuro.5b00063. Epub 2015 Apr 20.


Many current therapies target G protein coupled receptors (GPCR), transporters, or ion channels. In addition to directly targeting these proteins, disrupting the protein-protein interactions that localize or regulate their function could enhance selectivity and provide unique pharmacologic actions. Regulators of G protein signaling (RGS) proteins, especially RGS4, play significant roles in epilepsy and Parkinson's disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3β, another target of this class of chemical scaffolds. It does not inhibit the cysteine protease papain at 100 μM. CCG-203769 enhances Gαq-dependent cellular Ca(2+) signaling in an RGS4-dependent manner. TDZD inhibitors also enhance Gαi-dependent δ-OR inhibition of cAMP production in SH-SY-5Y cells, which express endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 mechanism of Gαi-dependent muscarinic bradycardia in vivo. Furthermore, it reverses raclopride-induced akinesia and bradykinesia in mice, a model of some aspects of the movement disorder in Parkinson's disease. A broad assessment of compound effects revealed minimal off-target effects at concentrations necessary for cellular RGS4 inhibition. These results expand our understanding of the mechanism and specificity of TDZD RGS inhibitors and support the potential for therapeutic targeting of RGS proteins in Parkinson's disease and other neural disorders.

Keywords: PPI; Parkinson’s disease; RGS; Regulator of G-protein signaling; protein−protein interaction; thiadiazolidinone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology*
  • Bradycardia / drug therapy
  • Bradycardia / physiopathology
  • Calcium / metabolism
  • Carbachol / pharmacology
  • Cell Line, Tumor
  • Cholinergic Agonists / pharmacology
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Papain / metabolism
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / physiopathology
  • RGS Proteins / antagonists & inhibitors*
  • RGS Proteins / metabolism
  • Raclopride
  • Rats, Sprague-Dawley


  • Antiparkinson Agents
  • Cholinergic Agonists
  • RGS Proteins
  • RGS4 protein
  • Raclopride
  • Carbachol
  • Cyclic AMP
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3
  • Papain
  • Calcium