# Discovery of mGlu receptor PAMs for treatment of schizophrenia

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $752,218

## Abstract

Recent clinical and preclinical, and human genetic studies suggest that selective positive allosteric
modulators (PAMs) of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor have exciting potential as
a novel approach for treatment of schizophrenia. We found that highly selective mGlu1 PAMs exert their
antipsychotic-like effects in animal models by selectively inhibiting dopamine (DA) release in the striatum but
not in extrastriatal regions, where inhibition of DA signaling could contribute to adverse effects of existing
antipsychotic agents. Furthermore, we present exciting new data showing that mGlu1 PAMs have specific
actions within the prefrontal cortex (PFC) that can reverse pathophysiological changes in specific cortical
circuits that are disrupted in schizophrenia patients, and can reverse specific cognitive and social deficits in
rodent models. Thus, mGlu1 PAMs could provide robust antipsychotic efficacy through actions of DA signaling,
and may also improve some negative symptoms and cognitive deficits in schizophrenia patients by reducing
pathophysiological changes in specific cortical circuits. It will now be important to optimize highly selective
mGlu1 PAMs that are suitable for advancing to clinical development to allow clinical studies to directly assess
the utility of these compounds as a novel strategy for treatment of schizophrenia. We recently made a major
breakthrough in discovery and optimization of multiple highly selective mGlu1 PAMs that have excellent drug-
like properties. These compounds provide exciting new drug leads that can provide the basis of a focused
effort to optimize novel mGlu1 PAMs that are suitable for advancing to preclinical and clinical development.
We have been highly successful in optimizing multiple selective ligands for other mGlu receptors and other
GPCR subtypes as drug candidates that are now advancing in preclinical and clinical development. This
places us in an excellent position to optimize selective mGlu1 PAMs as drug candidates for treatment of
positive symptoms associated with schizophrenia and to further assess the potential utility of these compounds
in reversing specific negative symptoms and cognitive deficits. We now propose a series of studies in which
we will optimize highly selective mGlu1 PAMs suitable for preclinical proof of concept studies and that have the
properties required so that they can subsequently be advanced IND-enabling studies and clinical development.

## Key facts

- **NIH application ID:** 9873098
- **Project number:** 5R01MH119673-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** P Jeffrey Conn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $752,218
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873098

## Citation

> US National Institutes of Health, RePORTER application 9873098, Discovery of mGlu receptor PAMs for treatment of schizophrenia (5R01MH119673-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873098. Licensed CC0.

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