Depression is a serious psychiatric disorder that remains a major public health problem. Approximately 21% of the general population suffers from depression sometime in their lifetime, while the incidence of depression is 30-37% in drug abusers. There has not been development of new antidepressants with novel pharmacological mechanisms of action for several decades. Recent publications and preliminary data reviewed in this application suggest that antagonists or negative allosteric modulators at metabotropic glutamate receptors (mGluR) Group II (mGluR2 and mGluR3) may have antidepressant properties. Thus, mGluR2/3 are novel targets for antidepressant treatment. This new revised R01 application is in response to PAR-07-048 entitled Drug Discovery for Nervous System Disorders that encourages the synthesis and preclinical testing of novel compounds for the prevention and treatment of nervous system disorders. A multidisciplinary research team comprised of chemists (Burnham Institute), in vitro pharmacologists (Vanderbilt University) and behavioral pharmacologists (University of California, San Diego) will focus on the synthesis and testing of new mGluR2/3 orthosteric antagonists and negative allosteric modulators as treatments for depression. Specific Aim 1 will involve the design and synthesis of novel mGluR2/3 orthosteric antagonists and negative allosteric modulators with optimized potency, selectivity, and in vivo activity. Specific Aim 2 will: i) evaluate and characterize the newly synthesized compounds for potency and efficacy at mGluR2, mGluR3, other mGluRs and various other central nervous system molecular targets, and ii) perform absorption, distribution, metabolism and excretion analyses, as well as evaluate blood brain barrier permeation and pharmacokinetics using in vitro and in vivo assays. Once the optimal mGluR2/3 compounds are identified (see Research Plan for criteria used to select compounds), Specific Aim 3 will investigate the effects of these selected compounds in animal models of: i) stress-induced anhedonia involving assessment of elevations in intracranial self-stimulation (ICSS) reward thresholds after chronic social defeat in rats; and ii) antidepressant-like activity in the forced swim test in rats. Anhedonia is defined as diminished interest or pleasure in rewarding stimuli and is considered a core behavioral phenotype of depression. Thus, compounds with demonstrated anti-anhedonic activity in the stress- induced anhedonia model or antidepressant-like activity in the forced swim test and which also exhibit drug-like properties will be considered putative drug candidates for future drug discovery and development efforts. Potential side-effects will be assessed in later years of the project, once drug-like candidates are identified. The proposed multidisciplinary research program is highly significant as it addresses an important public health problem, innovative as it focuses on Group II mGluRs as targets for novel antidepressants, and timely as it is in response to a Program Announcement by NIH. Therefore, this research program has the potential for a significant scientific and medical impact by contributing to the discovery of new medications for depression. PUBLIC HEALTH RELEVANCE: Depression is a serious psychiatric disorder that affects a large percentage of the USA population. The proposed project will synthesize new compounds that will target metabotropic glutamate receptors in the brain and evaluate them for their putative antidepressant activity in animal models of depression. This project is very innovative and promises to have a highly significant overall impact by promoting the discovery of new treatments for this devastating disorder.