A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

Selvam, Chelliah; Oueslati, Nadia; Lemasson, Isabelle; Brabet, Isabelle; Courtiol, Tiphanie; Cesarini, Sara; Triballeau, Nicolas; Bertrand, Hugues‐Olivier; Goudet, Cyril; Pin, Jean‐Philippe; Acher, Francine

doi:10.1021/jm901523t

Cited by 62 publications

(67 citation statements)

References 44 publications

(159 reference statements)

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“…Mutagenesis data confirmed that cinnabarinic acid binds to the orthosteric site of mGlu4 receptor. Cinnabarinic acid was thus docked in the mGlu4 receptor closed extracellular domain homology model that we described previously (Selvam et al, 2010). The molecule fits nicely in the cleft between the two lobes close to the hinge (Fig.…”

Section: Resultsmentioning

confidence: 82%

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Cinnabarinic Acid, an Endogenous Metabolite of the Kynurenine Pathway, Activates Type 4 Metabotropic Glutamate Receptors

Fazio¹,

Lionetto²,

Molinaro³

et al. 2012

Mol Pharmacol

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Cinnabarinic acid is an endogenous metabolite of the kynurenine pathway that meets the structural requirements to interact with glutamate receptors. We found that cinnabarinic acid acts as a partial agonist of type 4 metabotropic glutamate (mGlu4) receptors, with no activity at other mGlu receptor subtypes. We also tested the activity of cinnabarinic acid on native mGlu4 receptors by examining 1) the inhibition of cAMP formation in cultured cerebellar granule cells; 2) protection against excitotoxic neuronal death in mixed cultures of cortical cells; and 3) protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice after local infusion into the external globus pallidus. In all these models, cinnabarinic acid behaved similarly to conventional mGlu4 receptor agonists, and, at least in cultured neurons, the action of low concentrations of cinnabarinic acid was largely attenuated by genetic deletion of mGlu4 receptors. However, high concentrations of cinnabarinic acid were still active in the absence of mGlu4 receptors, suggesting that the compound may have off-target effects. Mutagenesis and molecular modeling experiments showed that cinnabarinic acid acts as an orthosteric agonist interacting with residues of the glutamate binding pocket of mGlu4. Accordingly, cinnabarinic acid did not activate truncated mGlu4 receptors lacking the N-terminal Venus-flytrap domain, as opposed to the mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino) cyclopropa[b-]chromen-1a-carboxamide (PHCCC). Finally, we could detect endogenous cinnabarinic acid in brain tissue and peripheral organs by high-performance liquid chromatography-tandem mass spectrometry analysis. Levels increased substantially during inflammation induced by lipopolysaccharide. We conclude that cinnabarinic acid is a novel endogenous orthosteric agonist of mGlu4 receptors endowed with neuroprotective activity.

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Section: Resultsmentioning

confidence: 82%

“…Cinnabarinic acid was docked in a homology model of mGlu4R amino terminal domain previously validated (Selvam et al, 2010). The ligand was initially positioned in the binding site using GOLD version 4.1 (http://www.ccdc.cam.ac.uk/ products/life_sciences/gold/).…”

Section: Molecular Modeling: Docking Of Cinnabarinic Acid In Mglu4 Ammentioning

confidence: 99%

Cinnabarinic Acid, an Endogenous Metabolite of the Kynurenine Pathway, Activates Type 4 Metabotropic Glutamate Receptors

Fazio¹,

Lionetto²,

Molinaro³

et al. 2012

Mol Pharmacol

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“…These small molecules are new allosteric modulators and are called extracellular domain allosteric modulators (EDAM). To date, there are three groups of EDAMs and their corresponding sites have been identified: IMP to the T1R1 VFT of the umami taste receptor [31] , SE-2/SE-3 to the T1R2 VFT of the sweet taste receptor [67] and the (R)-PCEP derivatives with long alkyl chains to the VFT of the mGlu4 receptor [68,69] .…”

Section: Tm Allosteric Sitesmentioning

confidence: 99%

Structure and ligand recognition of class C GPCRs

2012

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The G-protein-coupled receptors (GPCRs) are one of the largest super families of cell-surface receptors and play crucial roles in virtually every organ system. One particular family of GPCRs, the class C GPCRs, is distinguished by a characteristically large extracellular domain and constitutive dimerization. The structure and activation mechanism of this family result in potentially unique ligand recognition sites, thereby offering a variety of possibilities by which receptor activity might be modulated using novel compounds. In the present article, we aim to provide an overview of the exact sites and structural features involved in ligand recognition of the class C GPCRs. Furthermore, we demonstrate the precise steps that occur during the receptor activation process, which underlie the possibilities by which receptor function may be altered by different approaches. Finally, we use four typical family members to illustrate orthosteric and allosteric sites with representative ligands and their corresponding therapeutic potential.

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“…At mGlu receptors, the glutamate-binding pocket is well conserved across the mGlu subtypes, encumbering the discovery selective orthosteric agonists and antagonists (Brauner-Osborne et al, 2007). However, recently, long alkyl chain containing derivatives of (R)-PCEP, a molecule discovered by virtual screening on the VFT of mGlu receptors, revealed a new binding pocket in mGlu 4 (Selvam et al, 2010). Indeed, these compounds not only bind in the glutamate-binding pocket itself, but may also interact with a novel, putative binding pocket adjacent to the glutamate-binding site.…”

Section: Group III Mglu Receptors and Their Ligandsmentioning

confidence: 99%