A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5.

  title={A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5.},
  author={Julie A O'brien and Wei Lemaire and Tsing-bau Chen and Raymond S. L. Chang and Marlene A. Jacobson and Sookhee N. Ha and Craig W. Lindsley and Herv{\'e} J. Schaffhauser and Cyrille Sur and Douglas J. Pettibone and P. Jeffrey Conn and David Williams},
  journal={Molecular pharmacology},
  volume={64 3},
We have identified a family of highly selective allosteric modulators of the group I metabotropic glutamate receptor subtype 5 (mGluR5). This family of closely related analogs exerts a spectrum of effects, ranging from positive to negative allosteric modulation, and includes compounds that do not themselves modulate mGluR5 agonist activity but rather prevent other family members from exerting their modulatory effects. 3,3'-Difluorobenzaldazine (DFB) has no agonist activity, but it acts as a… 
A Novel Class of Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Interact with a Site Distinct from That of Negative Allosteric Modulators
Analysis of CDPPB analogs and site-directed mutagenesis suggest that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGLUR1 potentiators.
A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain
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.
A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models
It is demonstrated that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGLUR5 activity in vivo.
A Novel Family of Potent Negative Allosteric Modulators of Group II Metabotropic Glutamate Receptors
Synthesis and characterization of a novel family of derivatives of dihydrobenzo[1,4]diazepin-2-one that are selective negative allosteric modulators for group II mGluRs are reported, suggesting that these two positive allosterics modulators of mGLUR2 may share a common binding site and that this site may be distinct from the binding site for the new negativeAllostericModulators of group IIMgluRs.
Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses
Exciting advances have been made in the discovery of selective positive allosteric modulators of the metabotropic glutamate receptor (mGluR) mGluR5. These compounds may provide a novel approach that
Discovery of a Novel Chemical Class of mGlu5 Allosteric Ligands with Distinct Modes of Pharmacology
We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu5) termed 4
Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator.
Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists.
Allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays and Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping.


BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity.
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.
Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site
  • F. Knoflach, V. Mutel, J. Kemp
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2001
Two chemical series of compounds acting as selective positive allosteric modulators of native and recombinant metabotropic glutamate 1 (mGlu1) receptors were identified, markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy.
CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding.
It is proposed that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain.
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*
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 Allosteric Binding Site of a Novel, Selective, Noncompetitive Antagonist of the Metabotropic Glutamate 1 Receptor*
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.
SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5.
Cell lines expressing the human metabotropic glutamate receptor subtype 5a and hmGluR1b were used as targets in an automated high-throughput screening system that measures changes in intracellular Ca2+ ([Ca2+]i) using fluorescence detection, and the first description of highly selective, noncompetitive mGLUR5 antagonists was described.
Pharmacological agents acting at subtypes of metabotropic glutamate receptors
[3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists.
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.
Pharmacology and functions of metabotropic glutamate receptors.
  • P. Conn, J. Pin
  • Biology
    Annual review of pharmacology and toxicology
  • 1997
The findings suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.