Animal and clinical studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) could provide a novel approach for the treatment of anxiety disorders and schizophrenia. However, group II mGlu receptor agonists activate both mGlu2 and mGlu3, and the relative contributions of these two receptor subtypes to the actions of these drugs are not known. Thus, there is a critical need to determine whether activation of a specific group II mGlu receptor subtype (mGlu2 or mGlu3) could elicit the behavioral and electrophysiological effects of group II mGlu receptor agonists that are relevant to their potential therapeutic efficacy. Furthermore, development of tolerance and adverse effects of direct agonists could limit their clinical use. Thus, it will be important to develop novel approaches to increasing activity of these receptors that may have advantages relative to direct agonists. In recent months, a novel class of compounds has been discovered that act as selective allosteric potentiators of the mGlu2 receptor subtype. These compounds do not activate mGlu2 directly but act at an allosteric site to potentiate glutamate-induced activation of the receptor. These compounds represent the first clear departure from glutamate analogs as mGlu2 activators are the first compounds that are highly selective for mGlu2 relative to mGlu3 or other mGlu receptor subtypes. However, the functional effects of these compounds in systems relevant to the therapeutic efficacy of group II mGlu receptor agonists have not been determined. We propose a series of studies in which we will determine the effects of allosteric potentiators of mGlu2 on electrophysiological responses to group II mGlu receptor activation in cell populations that have been postulated to be important for the therapeutic effects of these compounds. In addition, we will systematically evaluate the behavioral effects of allosteric mGlu2 potentiators in animal models predictive of anxiolytic and antipsychotic activity. Finally, we will determine whether direct agonists and allosteric potentiators differ in their propensity to induce desensitization and behavioral tolerance after chronic administration. These studies will build on the exciting advances suggesting a potential therapeutic utility of group II mGlu receptor activators and could provide a novel approach to increasing activity of these receptors that for development of new therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH074953-05
Application #
7871387
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Winsky, Lois M
Project Start
2006-06-01
Project End
2012-05-31
Budget Start
2010-06-17
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$253,382
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Xiang, Zixiu; Conn, P Jeffrey (2016) Novel PAMs Targeting NMDAR GluN2A Subunit. Neuron 89:884-6
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
Gogliotti, Rocco D; Engers, Darren W; Garcia-Barrantes, Pedro M et al. (2016) Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy. Bioorg Med Chem Lett 26:2915-2919
Balu, Darrick T; Li, Yan; Takagi, Shunsuke et al. (2016) An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology 41:2052-61
Rook, Jerri M; Xiang, Zixiu; Lv, Xiaohui et al. (2015) Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents. Neuron 86:1029-1040
Bridges, Thomas M; Rook, Jerri M; Noetzel, Meredith J et al. (2013) Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. Drug Metab Dispos 41:1703-14
Rook, Jerri M; Noetzel, Meredith J; Pouliot, Wendy A et al. (2013) Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity. Biol Psychiatry 73:501-9
Johnson, Kari A; Niswender, Colleen M; Conn, P Jeffrey et al. (2011) Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata. Neurosci Lett 504:102-106
Gregory, Karen J; Dong, Elizabeth N; Meiler, Jens et al. (2011) Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology 60:66-81
Field, Julie R; Walker, Adam G; Conn, P Jeffrey (2011) Targeting glutamate synapses in schizophrenia. Trends Mol Med 17:689-98

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