Signal transduction via guanine nucleotide binding proteins (G proteins) is central to the function of drugs of abuse such as opioids, cannabinoids, and dopamine modulators (cocaine and amphetamine). A novel family of proteins, Regulators of G Protein Signaling - RGS Proteins, strongly suppresses signaling by inhibitory G proteins that are involved in the actions of these drugs of abuse. In particular RGS9 knock-out mice show dramatically enhanced responses to amphetamine, cocaine, and morphine. The availability of chemical modulators of RGS proteins will enhance our understanding of physiological and pharmacological roles of RGS proteins in the actions of drugs of abuse. Such RGS modulators will validate the potential of RGS proteins as a novel target of drug action and could provide compounds to serve as leads for therapeutics. ? ? We have recently devised high-throughput screens for modulators of the RGS/G1 interaction and identified two series of micromolar inhibitors of RGS4. In this project, we will: 1) evaluate the molecular mechanisms of RGS inhibition by these compound and undertake further high throughput screening for additional inhibitors or activators of RGS4 and RGS9, 2) determine structure-activity relations, define pharmacophore models, and optimize in vitro potency, cellular activity, and predicted pharmacokinetic properties of identified compounds, and 3) examine these compounds in transfected cell model systems and brain slices and optimize structures for biological activity. This project will provide the initial steps and proof of principle for medications development targeting RGS proteins - a key modulator of signaling related to drug abuse. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA023252-01A1
Application #
7371562
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2007-09-30
Project End
2012-08-31
Budget Start
2007-09-30
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$321,049
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Shen, Weixing; Plotkin, Joshua L; Francardo, Veronica et al. (2015) M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. Neuron 88:762-73
Blazer, Levi L; Storaska, Andrew J; Jutkiewicz, Emily M et al. (2015) Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS Chem Neurosci 6:911-9
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Vashisth, Harish; Storaska, Andrew J; Neubig, Richard R et al. (2013) Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule. ACS Chem Biol 8:2778-84
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Storaska, Andrew J; Neubig, Richard R (2013) NMR methods for detection of small molecule binding to RGS4. Methods Enzymol 522:133-52
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Turner, Emma M; Blazer, Levi L; Neubig, Richard R et al. (2012) Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med Chem Lett 3:146-150
Blazer, Levi L; Zhang, Haoming; Casey, Emma M et al. (2011) A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. Biochemistry 50:3181-92

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