The metabotropic glutamate receptor (mGluR) mGluR5 subtype plays a critical role in regulating the rewarding effects of drugs of abuse and recent studies suggest that selective mGluR5 antagonists may provide an exciting new approach for treatment of addictive disorders. We have identified multiple new mGluR5 antagonists, including multiple unique scaffolds as well as compounds based on existing scaffolds that have novel activities. Most notably, we discovered a novel class of compounds that act as highly selective partial antagonists of mGluR5. Unlike partial agonists that have been identified for other receptors, these compounds do not activate the receptor to any level. However, they partially block activation of the receptor by glutamate without fully blocking receptor activation. We now have multiple partial antagonists that block mGluR5 with a range of activities from 10% to 90% inhibition when the allosteric binding site on the receptor is fully occupied. This exciting breakthrough would not be possible with traditional competitive orthosteric site antagonists but is achieved by targeting the allosteric antagonist site. By employing high throughput medicinal chemistry techniques we will optimize these screening leads into compounds suitable for proof of concept studies. These novel compounds will provide an unprecedented opportunity for our labs to determine whether partial blockade of mGluR5 will have effects in animal models that predict efficacy in treatment of cocaine abuse or whether complete blockade of the receptor is required. Also, these agents will allow us to directly evaluate the adverse effects of mGluR5 antagonists that possess different levels of mGluR5 blockade. In addition, our new understanding of partial antagonist activity will allow us to optimize compounds belonging to existing partial antagonist scaffolds as well as novel chemical classes to identify optimal properties to be used as research tools and drug leads. This research has direct relevance to the mission of NIDA and has the potential to impact human health directly. Our goal for this project is to develop a partial mGluR5 antagonist with an acceptable profile for preclinical and ultimately clinical development that may become a new drug to treat addictive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023947-05
Application #
8262403
Study Section
Special Emphasis Panel (ZDA1-MXS-M (17))
Program Officer
Shih, Ming L
Project Start
2008-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$394,370
Indirect Cost
$137,451
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D et al. (2018) Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett 28:1679-1685
Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D et al. (2017) Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett 27:4858-4866
Felts, Andrew S; Rodriguez, Alice L; Blobaum, Anna L et al. (2017) Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation. J Med Chem 60:5072-5085
Nickols, Hilary Highfield; Yuh, Joannes P; Gregory, Karen J et al. (2016) VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy. J Pharmacol Exp Ther 356:123-36
Crouch, Rachel D; Morrison, Ryan D; Byers, Frank W et al. (2016) Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity. Drug Metab Dispos 44:1296-303
Lindsley, Craig W; Emmitte, Kyle A; Hopkins, Corey R et al. (2016) Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors. Chem Rev 116:6707-41
Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D et al. (2016) N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents. Bioorg Med Chem Lett 26:1894-900
Gould, Robert W; Amato, Russell J; Bubser, Michael et al. (2016) Partial mGlu? Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects. Neuropsychopharmacology 41:1166-78
Gregory, Karen J; Conn, P Jeffrey (2015) Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation. Mol Pharmacol 88:188-202
Zhou, Ya; Malosh, Chrysa; Conde-Ceide, Susana et al. (2015) Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound. Bioorg Med Chem Lett 25:3515-9

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