ArticleLetters in drug design & discovery2019
Challenges in the Discovery and Optimization of mGlu
Article in Letters in drug design & discovery, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Metabotropic glutamate receptor homo- and heterodimers exhibit distinct responses to orthosteric and allosteric ligands.Molecular pharmacology · 2025Article
- Novel 6-Aryl isoindolin-1-one Derivatives as Negative Allosteric Modulators of Metabotropic Glutamate Receptor 2.ACS medicinal chemistry letters · 2025Article
- 6-Aryl Isoindolin-1-ones: Novel mGluR2 Negative Allosteric Modulators.ACS medicinal chemistry letters · 2025Article
- Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGluInternational journal of molecular sciences · 2023Article
- Allosteric Molecular Switches in Metabotropic Glutamate Receptors.ChemMedChem · 2021Review
- Regulation of Glutamatergic Activity via Bidirectional Activation of Two Select Receptors as a Novel Approach in Antipsychotic Drug Discovery.International journal of molecular sciences · 2020Review
- Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGluBioorganic & medicinal chemistry letters · 2020Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
backgroundThis article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs).
methodsInitial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu
resultsHowever, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu
conclusionThese results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.
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Registered trials
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