Major Depressive Disorder (MDD) affects approximately 16% of Americans and represents one of the most common causes of disability worldwide. Unfortunately, less than one third of patients experience sustained remission of MDD symptoms with currently available medications. Recent studies have raised the exciting possibility that highly selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate receptor mGlus subtype may provide a novel approach to the treatment of MDD. This mechanism represents a fundamental departure from existing therapies and has the potential to provide more rapid onset than existing therapies and may provide sustained relief for refractory patients. In this revised NCDDG application, we propose studies aimed at using our novel mGlus NAMs discovered at the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) to further validate this mechanism in animal models and perform translational studies that can support a future clinical development effort. In addition, we will optimize novel mGlus NAMs to achieve properties required to select a lead clinical development candidate and backup compounds. This will require coordinated efforts of two major projects and support of 2 cores. Project 1 will focus on animal studies aimed at further characterizing the behavioral effects and CNS occupancy of novel mGlus NAMs. In Project 2, we will chemically optimize novel mGlus NAMs based on this scaffold to achieve a balance of properties required to select a clinical development candidate that can advance to IND-enabling studies and clinical development. These projects will be supported by two cores, including a Bioanalytical and DMPK Core (Core A) and Administrative Core (Core B).

Public Health Relevance

Successful completion of this highly interdisciplinary effort will provide critical preclinical information for the validation of a novel therapeutic strategy through antagonism of mGluR5 for the potential treatment of symptoms associated with MDD and a highly optimization of mGlus NAM preclinical candidate and backups for future clinical studies in MDD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19MH097056-01A1
Application #
8434427
Study Section
Special Emphasis Panel (ZMH1-ERB-C (05))
Program Officer
Brady, Linda S
Project Start
2013-01-08
Project End
2015-11-30
Budget Start
2013-01-08
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$1,340,109
Indirect Cost
$481,065
Name
Vanderbilt University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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