A Novel Class of Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Interact with a Site Distinct from That of Negative Allosteric Modulators

  title={A Novel Class of Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Interact with a Site Distinct from That of Negative Allosteric Modulators},
  author={Kamondanai Hemstapat and Tomas de Paulis and Yelin Chen and Ashley E. Brady and Vandana K. Grover and David Alagille and Gilles Tamagnan and P. Jeffrey Conn},
  journal={Molecular Pharmacology},
  pages={616 - 626}
We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CD-PPB), that act as positive allosteric modulators (potentiators) of metabotropic glutamate receptor (mGluR) subtype 5. Studies of CDPPB analogs revealed that some compounds in this series serve also as positive allosteric modulators of mGluR1. Although CDPPB is selective for mGluR5 relative to other mGluR subtypes, several CDPPB analogs also showed 2.5-fold potentiation of… 
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
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.
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
Both electrophysiological and in vivo studies indicate the mGlu1 ago- PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGLU5 ago-PAMS/Pams and maintain temporal activity suggesting a broader therapeutic window.
Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity
Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mR5 ligands.
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.
A fluorescence-based high-throughput screening assay is used to screen an allosteric modulator-biased library of compounds to generate structurally diverse mGlu₁ negative allosterIC modulator hits for chemical optimization and provides valuable insight into the pharmacology underlying the disconnect between rat and human mGLU⁁ activity.
Discovery and Characterization of Novel Allosteric Potentiators of M1 Muscarinic Receptors Reveals Multiple Modes of Activity
Several novel ligands that potentiated agonist activation of M1 with low micromolar potencies and induced 5-fold or greater leftward shifts of the acetylcholine (ACh) concentration-response curve are identified, suggesting that structurally diverse M1 potentiators may act by distinct mechanisms and differentially regulate receptor coupling to downstream signaling pathways.
Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence
On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration.
Extracellular Calcium Modulates Actions of Orthosteric and Allosteric Ligands on Metabotropic Glutamate Receptor 1α*
The present study shows that the previously predicted Ca2+-binding site in the hinge region of mGluR1α is adjacent to the site where orthosteric agonists and antagonists bind on the extracellular domain of the receptor, which modulates not only glutamate-evoked signaling but also the actions of both Orthosteric ligands and allosteric modulators on mGLUR1 α.
“Selective” Class C G Protein-Coupled Receptor Modulators Are Neutral or Biased mGlu5 Allosteric Ligands
It is found that for many class C GPCR allosteric modulators, subtype selectivity is driven by cooperativity and misinterpreted owing to unappreciated bias.


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.
Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo.
Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotic based on the NMDA hypofunction model for schizophrenia.
A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5.
Evidence that allosteric sites on GPCRs can respond to closely related ligands with a range of pharmacological activities from positive to negative modulation as well as to neutral competition of this modulation is provided.
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 Close Structural Analog of 2-Methyl-6-(phenylethynyl)-pyridine Acts as a Neutral Allosteric Site Ligand on Metabotropic Glutamate Receptor Subtype 5 and Blocks the Effects of Multiple Allosteric Modulators
Three novel compounds that bind to the allosteric 2-methyl-6-(phenylethynyl)-pyridine (MPEP) site on mGlu5 but have only partial inhibition or no functional effects on the mGLU5 response are reported.
Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes.
The structure-activity relationships showed that electronegative aromatic substituents in the para-position of the benzamide moiety of CDPPB increase potency and both binding and functional activities were further increased with a halogen atom in the ortho- position of the 1-phenyl ring.
Biphenyl-indanone A, a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor Subtype 2, Has Antipsychotic- and Anxiolytic-Like Effects in Mice
Results indicate that BINA is a selective mGluR2 positive allosteric modulator and provide further support for the growing evidence that selective allosterics potentiators of mGLUR2 mimic many of the in vivo actions of m GluR 2/3 agonists that may predict therapeutic utility of these compounds.
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.
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.