RGD Reference Report - Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. - Rat Genome Database

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

Authors: Blazer, Levi L  Storaska, Andrew J  Jutkiewicz, Emily M  Turner, Emma M  Calcagno, Mariangela  Wade, Susan M  Wang, Qin  Huang, Xi-Ping  Traynor, John R  Husbands, Stephen M  Morari, Michele  Neubig, Richard R 
Citation: Blazer LL, etal., ACS Chem Neurosci. 2015 Jun 17;6(6):911-9. doi: 10.1021/acschemneuro.5b00063. Epub 2015 Apr 20.
RGD ID: 13524517
Pubmed: PMID:25844489   (View Abstract at PubMed)
DOI: DOI:10.1021/acschemneuro.5b00063   (Journal Full-text)

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-3ß, 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 d-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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RGS4HumanParkinsonism treatmentISORgs4 (Mus musculus) RGD 
Rgs4RatParkinsonism treatmentISORgs4 (Mus musculus) RGD 
Rgs4MouseParkinsonism treatmentIMP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rgs4Ratpositive regulation of heart rate  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rgs4  (regulator of G-protein signaling 4)

Genes (Mus musculus)
Rgs4  (regulator of G-protein signaling 4)

Genes (Homo sapiens)
RGS4  (regulator of G protein signaling 4)


Additional Information