ArticleACS chemical neuroscience2014
A novel class of succinimide-derived negative allosteric modulators of metabotropic glutamate receptor subtype 1 provides insight into a disconnect in activity between the rat and human receptors.
Article in ACS chemical neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 54 citations in OpenAlex.
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- Small-molecule probe for IBD risk variant GPR65 I231L alters cytokine signaling networks through positive allosteric modulation.Science advances · 2024Article
- Palladium-catalyzed intramolecular aza-Wacker-type cyclization of vinyl cyclopropanecarboxamides to access conformationally restricted aza[3.1.0]bicycles.RSC advances · 2023Article
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- Intramolecular nucleophilic addition of carbanions generated from N-benzylamides to cyclopropenes.Organic & biomolecular chemistry · 2018Article
- Synthesis of Succinimide Derivatives by NHC-Catalyzed Stetter Reaction of Aromatic Aldehydes withACS omega · 2017Article
- Co(III)-Catalyzed C-H Activation: A Site-Selective Conjugate Addition of Maleimide to Indole at the C-2 Position.ACS omega · 2017Article
- Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.Chemical reviews · 2016Review
- Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.Bioorganic & medicinal chemistry letters · 2016Article
- N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents.Bioorganic & medicinal chemistry letters · 2016Article
- Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis.Scientific reports · 2016Article
- The Role of mGlu Receptors in Hippocampal Plasticity Deficits in Neurological and Psychiatric Disorders: Implications for Allosteric Modulators as Novel Therapeutic Strategies.Current neuropharmacology · 2016Review
- Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics.Journal of medicinal chemistry · 2015Article
- Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs.Molecules (Basel, Switzerland) · 2015Article
- Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics.ACS chemical biology · 2014Article
- 2013 Philip S. Portoghese Medicinal Chemistry Lectureship: drug discovery targeting allosteric sites.Journal of medicinal chemistry · 2014Article
- Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders.Nature reviews. Drug discovery · 2014Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Recent progress in the discovery of mGlu₁ allosteric modulators has suggested the modulation of mGlu₁ could offer possible treatment for a number of central nervous system disorders; however, the available chemotypes are inadequate to fully investigate the therapeutic potential of mGlu₁ modulation. To address this issue, we used a fluorescence-based high-throughput screening assay to screen an allosteric modulator-biased library of compounds to generate structurally diverse mGlu₁ negative allosteric modulator hits for chemical optimization. Herein, we describe the discovery and characterization of a novel mGlu₁ chemotype. This series of succinimide negative allosteric modulators, exemplified by VU0410425, exhibited potent inhibitory activity at rat mGlu₁ but was, surprisingly, inactive at human mGlu₁. VU0410425 and a set of chemically diverse mGlu₁ negative allosteric modulators previously reported in the literature were utilized to examine this species disconnect between rat and human mGlu₁ activity. Mutation of the key transmembrane domain residue 757 and functional screening of VU0410425 and the literature compounds suggests that amino acid 757 plays a role in the activity of these compounds, but the contribution of the residue is scaffold specific, ranging from critical to minor. The operational model of allosterism was used to estimate the binding affinities of each compound to compare to functional data. This novel series of mGlu₁ negative allosteric modulators provides valuable insight into the pharmacology underlying the disconnect between rat and human mGlu₁ activity, an issue that must be understood to progress the therapeutic potential of allosteric modulators of mGlu₁.
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