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Selectivity and Anti-Parkinson’s Potential of Thiadiazolidinone RGS4 Inhibitors

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Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States,
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, United States
§ Department of Pharmacy and Pharmacology, University of Bath, Bath, U.K.
Section of Pharmacology, Department of Medical Science, University of Ferrara, Ferrara, Italy 44121
National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, United States
*Department of Pharmacology & Toxicology, Michigan State University, B440 Life Sciences, 1355 Bogue St., East Lansing, MI 48824. Phone: 517 353-7145. Fax: 517 353-8915. E-mail: [email protected]
Cite this: ACS Chem. Neurosci. 2015, 6, 6, 911–919
Publication Date (Web):April 6, 2015
https://doi.org/10.1021/acschemneuro.5b00063
Copyright © 2015 American Chemical Society

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    Abstract

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    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 Ca2+ 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.

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