Regulators of G protein signaling (RGS proteins) are critical modulators of signaling through the G protein coupled receptor (GPCR) family. GPCRs are the targets of a significant number of clinically used drugs including most drugs of abuse and RGS protein activity generally suppresses their function. Overexpression of RGS4 has been reported in rodent neuropathic pain models and abused drugs such as opioids and psychostimulants also affect RGS protein expression. Inhibition of RGS proteins can produce tissue-specific enhancement of GPCR agonist function with the potential to improve their specificity and reduce side-effects. The long term goals of this project are to discover small molecule chemical modulators of RGS protein activity - either to inhibit or enhance their function. This competitive revision (supplement) application takes off from our successful discovery of highly potent RGS4 inhibitors that have activity in vivo. This represents the first successful chemical targeting of RGS proteins.
The specific aims of the present study are to: 1) establish whether the in vivo actions of the new RGS4 inhibitors are mediated through RGS4 by studies in RGS4 knockout mice, 2) determine whether our novel RGS4 inhibitors can enhance the analgesic actions of delta-opioid agonists which currently have limited efficacy. These studies would provide proof-of-principle for this novel approach to improving pharmacotherapy by chemically targeting RGS proteins.

Public Health Relevance

Narcotic analgesics, including morphine and heroin, are major drugs of abuse. They are important for control of pain and their actions are modulated inside the cell by a newly discovered mechanism. We have just developed inhibitors of that mechanism that could provide improved pain relief with a unique class of opiate drugs that may have decreased abuse potential.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA023252-05S1
Application #
8237614
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2007-04-01
Project End
2013-08-31
Budget Start
2012-02-15
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$112,863
Indirect Cost
$36,774
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
Storaska, Andrew J; Mei, Jian P; Wu, Meng et al. (2013) Reversible inhibitors of regulators of G-protein signaling identified in a high-throughput cell-based calcium signaling assay. Cell Signal 25:2848-55
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
Storaska, Andrew J; Neubig, Richard R (2013) NMR methods for detection of small molecule binding to RGS4. Methods Enzymol 522:133-52
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
Blazer, Levi L; Roman, David L; Chung, Alfred et al. (2010) Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins. Mol Pharmacol 78:524-33
Roman, David L; Blazer, Levi L; Monroy, C Aaron et al. (2010) Allosteric inhibition of the regulator of G protein signaling-Galpha protein-protein interaction by CCG-4986. Mol Pharmacol 78:360-5
Blazer, Levi L; Neubig, Richard R (2009) Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: current progress and future hurdles. Neuropsychopharmacology 34:126-41
Roof, Rebecca A; Roman, David L; Clements, Samuel T et al. (2009) A covalent peptide inhibitor of RGS4 identified in a focused one-bead, one compound library screen. BMC Pharmacol 9:9
Roman, David L; Ota, Shodai; Neubig, Richard R (2009) Polyplexed flow cytometry protein interaction assay: a novel high-throughput screening paradigm for RGS protein inhibitors. J Biomol Screen 14:610-9

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