Identification of a novel transmembrane domain involved in the negative modulation of mGluR1 using a newly discovered allosteric mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one

@article{Fukuda2009IdentificationOA,
  title={Identification of a novel transmembrane domain involved in the negative modulation of mGluR1 using a newly discovered allosteric mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one},
  author={Junko Fukuda and Gentaroh Suzuki and Toshifumi Kimura and Yasushi Nagatomi and Satoru Ito and Hiroshi Kawamoto and Satoshi Ozaki and Hisashi Ohta},
  journal={Neuropharmacology},
  year={2009},
  volume={57},
  pages={438-445}
}
ONIOM and FMO-EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site
The crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazol-2-yl)-N-methylbenzamide (FITM, a negative allosteric
Metabotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
TLDR
Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain, without significantly activating the receptor in the absence of agonist.
Detailed In Vitro Pharmacological Characterization of Clinically Tested Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5
TLDR
This study is the first to measure mGLU5 NAM binding kinetics and negative allosteric modulation of mGlu5 receptor internalization and adds significant new knowledge about the molecular pharmacology of a diverse range of clinically relevant NAMs.
Structure-function studies of the metabotropic glutamate receptor type 6 (mGluR6) and comparison with rhodopsin
TLDR
Support for the hypothesis that these two GPCRs may share a general mechanism of activation despite the large sequence divergence was obtained from computational sequence analysis which showed that the highly ranking residues involved in long-range interaction in rhodopsin overlap with the allosteric binding pocket of mGluR6.
Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs
TLDR
The applicability of molecular simulation technologies for discovering potential natural mGluR1 NAMs from Chinese herbs is indicated and thesinine-4ʹ-O-β-d-glucoside, nigrolineaxanthone-P and nodakenin might exhibit negative allosteric moderating effects on mGLUR1.
Probing the Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a “Molecular Switch” in PAM Pharmacology
TLDR
Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity.
Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4.
TLDR
It is confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data and may provide a molecular basis for theymmetric signal transduction of mGlus, and insights into receptor signalling of class C GPCRs are offered.
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References

SHOWING 1-10 OF 27 REFERENCES
Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)
TLDR
FTIDC is a highly potent and selective allosteric mGluR1 antagonist and a compound having oral activity without species differences in its antagonistic activity on recombinant human, mouse, and rat mGlamR1 and could be a valuable tool for elucidating the functions of mGLUR1 not only in rodents but also in humans.
A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain
TLDR
It is found that allosteric potentiation of mGluR5 increases the effect of threshold agonist concentrations in native systems and potentiated NMDA receptor currents in hippocampal slices induced by threshold levels of DHPG, whereas having no effect on these currents by itself.
Radioligand Binding Properties and Pharmacological Characterization of 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a High-Affinity, Selective, and Noncompetitive Antagonist of Metabotropic Glutamate Receptor Type 1
TLDR
YM-298198 is a newly synthesized, high-affinity, selective, and noncompetitive antagonist of mGluR1 that will be a useful pharmacological tool due to its highly active properties in vitro and in vivo.
Mutational Analysis and Molecular Modeling of the Allosteric Binding Site of a Novel, Selective, Noncompetitive Antagonist of the Metabotropic Glutamate 1 Receptor*
TLDR
A striking conservation in the position of critical residues of the EM-TBPC-binding pocket of the mGlu1 receptor is observed, validating the rhodopsin crystal structure as a template for the family 3 G-protein-coupled receptors.
Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2.
TLDR
It is proposed that this allosteric binding site defines a pocket that is different from the orthosteric site located in the amino terminal domain at hmGluR2, and is also observed to a greater extent on the concentration-response curves to selective hmR2/3 agonists.
The Non-competitive Antagonists 2-Methyl-6-(phenylethynyl)pyridine and 7-Hydroxyiminocyclopropan[b]chromen-1a-carboxylic Acid Ethyl Ester Interact with Overlapping Binding Pockets in the Transmembrane Region of Group I Metabotropic Glutamate Receptors*
TLDR
Results indicate that MPEP and CPCCOEt bind to overlapping binding pockets in the TM region of group I mGluRs but interact with different non-conserved residues.
Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine.
TLDR
A striking similarity between the critical residues involved in MPEP-binding site with those of previously identified as 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile-binding pocket of mGlu1 is pointed to a common mechanism of inhibition shared by both antagonists.
BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity.
TLDR
BAY36-7620 will be useful to further delineate the functional importance of the mGlu1 receptor, including its putative agonist-independent activity, andTransmembrane helices 4 to 7 are shown to play a critical role in the selectivity of BAY36- 7620.
[3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists.
TLDR
The high affinity and selectivity of [(3)H]R214127 for mGlu1 receptors renders this compound the ligand of choice to study the native mGLU1 receptor in brain.
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