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Updated: Apr 25, 2026
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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
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SAR studies on mGlu5 receptor positive allosteric modulators (2003- 2013)
1Discovery Chemistry Research and Technologies, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA. haoju@lilly.com.
Current Topics in Medicinal Chemistry
|September 2, 2014
Summary
Positive allosteric modulators (PAMs) targeting metabotropic glutamate receptor 5 (mGlu5) show promise for schizophrenia treatment. Research reviews structure-activity relationships of mGlu5 PAMs, highlighting progress and clinical development challenges.
Area of Science:
- Neuroscience
- Pharmacology
- Medicinal Chemistry
Background:
- Metabotropic glutamate receptor 5 (mGlu5) is a G-protein-coupled receptor implicated in NMDA receptor function.
- mGlu5 receptor activation, via orthosteric or allosteric sites, enhances NMDA receptor function, offering a therapeutic target for schizophrenia.
Purpose of the Study:
- To comprehensively review structure-activity relationship (SAR) progress for mGlu5 positive allosteric modulators (PAMs).
- To highlight in vivo studies and discuss challenges in the clinical development of mGlu5 PAMs.
Main Methods:
- Review of primary and patent literature on mGlu5 PAMs.
- Analysis of structure-activity relationships (SAR) for identified chemical scaffolds.
- Inclusion of in vivo study data for select compounds.
Main Results:
- Significant progress in discovering diverse chemical scaffolds for mGlu5 PAMs over the past decade.
- Identification of multiple allosteric binding sites within the 7-TM domain of mGlu5 receptors.
- Novel insights into the biology of mGlu5 receptor allosteric activation.
Conclusions:
- mGlu5 PAMs represent a promising therapeutic strategy for schizophrenia.
- Continued SAR studies and in vivo investigations are crucial for advancing mGlu5 PAMs.
- Overcoming clinical development challenges is essential for realizing the therapeutic potential of mGlu5 PAMs.
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