Major depressive disorder (MDD) is a debilitating psychiatric illness that affects approximately 16% of the population worldwide and is associated with symptoms of depressed mood and anhedonia. Currently available antidepressant therapies, which work through enhancement of synaptic biogenic amine levels, provide limited symptomatic remission and are associated with delayed onset of action and dose-limiting side-effects in MDD patients. Recent clinical findings with antagonists of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) have reported robust and rapid efficacy in patients with MDD, particularly in treatment resistant populations. However, these direct-acting NMDAR antagonists are also associated with adverse side-effects that limit their clinical utility. Alternatively, the metabotropic glutamate receptor subtype 5 (mGluRs) is a close downstream signaling partner of the NMDAR;and antagonism of mGluRs results in inhibition of NMDAR signaling suggesting that mGluRs antagonists may provide an exciting new approach for the treatment of MDD. Recently, our group has been successful in the development of a highly selective series of mGluRs negative allosteric modulators (NAM), represented by VU0409106, that are now optimized as novel in vivo tools for further validation of the potential for mGluRs NAMs in MDD. In project 1 of this NCDDG, we will evaluate VU0409106 in several well established preclinical models of antidepressant-like activity and establish the degree of target engagement of central mGluRs necessary to observe efficacy using the selective mGluRs radiolig and [ H]m-PEPy. We will also evaluate the effects of VU0409106 in several preclinical models of anhedonia, which may be more relevant for evaluating novel mechanisms for antidepressant effects. Finally, we will assess the potential for VU0409106 to produce adverse effects associated with excessive NMDAR antagonism to establish the therapeutic index for the mechanism of this ligand.
To date, there has been limited success in the development of novel antidepressant therapies that provide a rapid onset of action and efficacy for the depressed mood and anhedonic symptoms observed in MDD patients. The studies outlined in project 1 of this NCDDG will provide a comprehensive preclinical data package for the validation and development of a novel therapeutic strategy through antagonism of mGluRs for the treatment of MDD and these studies will be critical to help guide the ongoing optimization of mGluRg NAM leads in project 2 of this application.
|Doria, Juliana G; de Souza, Jessica M; Silva, Flavia R et al. (2018) The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease. J Neurochem 147:222-239|
|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|
|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|
|Nedelcovych, Michael T; Gould, Robert W; Zhan, Xiaoyan et al. (2015) A rodent model of traumatic stress induces lasting sleep and quantitative electroencephalographic disturbances. ACS Chem Neurosci 6:485-93|
|Gregory, Karen J; Nguyen, Elizabeth D; Malosh, Chrysa et al. (2014) Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site. ACS Chem Neurosci 5:282-95|
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