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BioAssay: AID 588721

Optimization of novel mGluR5 positive allosteric modulators (PAM)s

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 subtype (mGluR5) have been identified as a potential novel approach to treatment for schizophrenia and other CNS disorders that lead to impaired cognitive function (1). These compounds exist across a variety of chemical scaffolds (2) and have been determined to interact with at least two distinct sites in the transmembrane region of the receptor (3). In addition, it has been observed in functional cell-based assays that different mGluR5 PAMs exhibit different properties (4). ..more
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AID: 588721
Data Source: Vanderbilt Specialized Chemistry Center (mGlu5_PAM_Summary)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2011-10-27
Modify Date: 2013-04-16
Target
Related Experiments
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AIDNameTypeProbeComment
588710mGluR5_3H_methoxyPEPy_BindingConfirmatory2 depositor-specified cross reference: Rat mGluR5 Competition Binding Assay (Secondary Assay 11)
588715Optimization of novel mGluR5 positive allosteric modulators with different mechanisms of action and modes of efficacyConfirmatory depositor-specified cross reference: Rat mGluR5 Ca+2 Mobilization Potency Assay (Secondary Assay 1)
588728rmGluR3_Thallium_Fold_Shift (GIRK)Other depositor-specified cross reference: Rat mGluR3 Thallium Fold Shift (Secondary Assay 4)
588730hmGluR6_Thallium_Fold_Shift (GIRK)Other depositor-specified cross reference: Human mGluR6 Thallium Fold Shift (Secondary Assay 7)
588731rmGluR7_Thallium_Fold_Shift (GIRK)Other depositor-specified cross reference: Rat mGluR7 Thallium Fold Shift (Secondary Assay 8)
588732rmGluR8_Thallium_Fold_Shift (GIRK)Other depositor-specified cross reference: Rat mGluR8 Thallium Fold Shift (Secondary Assay 9)
588733rmGluR2_Thallium_Fold_Shift (GIRK)Other depositor-specified cross reference: Rat mGluR2 Thallium Fold Shift (Secondary Assay 3)
588734rmGluR4_Thallium_Fold_Shift (GIRK)Other depositor-specified cross reference: Rat mGluR4 Thallium Fold Shift (Secondary Assay 5)
588735rmGluR5_Calcium_Fold_ShiftOther depositor-specified cross reference: Rat mGluR5 Calcium Fold Shift (Secondary Assay 6)
588736rmGluR1_Calcium_Fold_ShiftOther depositor-specified cross reference: Rat mGluR1 Calcium Fold Shift (Secondary Assay 2)
588737hmGluR5_Calcium_Fold_ShiftOther depositor-specified cross reference: Human mGluR5 Calcium Fold Shift (Secondary Assay 10)
588753ML254 and ML273 Competition in Radioligand Binding assays (Riserca)Other depositor-specified cross reference: ML254 and ML273 Competition in Radioligand Binding assays (Riserca)
651835Identification of a glycine sulfonamide based non-MPEP site positive allosteric potentiator (PAM) of mGlu5 (calcium_assay)Confirmatory16 depositor-specified cross reference
651852Identification of a glycine sulfonamide based non-MPEP site positive allosteric potentiator (PAM) of mGlu5 (binding_assay)Confirmatory depositor-specified cross reference
652185Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: rat mGlu2 selectivity AssayConfirmatory depositor-specified cross reference: Rat mGlu2 Selectivity Assay
652186Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: rat mGlu8 selectivity AssayConfirmatory depositor-specified cross reference: Rat mGlu8 Selectivity Assay
652191Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: 3pt binding AssayConfirmatory1 depositor-specified cross reference: 3pt Binding Assay
652196Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: full Ki determinationConfirmatory1 depositor-specified cross reference: Full Ki determination
652198Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: Fold-shift AssayConfirmatory1 depositor-specified cross reference: Fold-shift Assay
652201Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: rat mGlu1 selectivity AssayConfirmatory depositor-specified cross reference: Rat mGlu1 Selectivity Assay
652202Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: rat mGlu3 selectivity AssayConfirmatory depositor-specified cross reference: Rat mGlu3 Selectivity Assay
652203Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: rat mGlu7 selectivity AssayConfirmatory depositor-specified cross reference: Rat mGlu7 Selectivity Assay
652204Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: rat mGlu4 selectivity AssayConfirmatory depositor-specified cross reference: Rat mGlu4 Selectivity Assay
652205Discovery of Novel Silent Allosteric Modulators (SAM) of the Metabotropic Glutamate Receptor 5: human mGlu6 selectivity AssayConfirmatory depositor-specified cross reference: Human mGlu6 selectivity Assay
686927ML353 Eurofin Panel Assay for mGlu5 SAM Inhibitor (Probe Compound)Other depositor-specified cross reference: Eurofins PanLabs Panel Assay
Description:
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 subtype (mGluR5) have been identified as a potential novel approach to treatment for schizophrenia and other CNS disorders that lead to impaired cognitive function (1). These compounds exist across a variety of chemical scaffolds (2) and have been determined to interact with at least two distinct sites in the transmembrane region of the receptor (3). In addition, it has been observed in functional cell-based assays that different mGluR5 PAMs exhibit different properties (4).

Most notably, some mGluR5 PAMs exhibit allosteric agonist activity whereas others are pure mGluR5 PAMs with no intrinsic agonist activity. In order to determine the significance of these differences in a physiological setting, it is necessary to develop compounds that possess these different characteristics that are also amenable to in vivo studies (good physicochemical and pharmacokinetic properties). We have proposed a series of aims to evaluate the effects of these compounds on signaling in the CNS and to test the hypothesis that mGluR5 PAMs enhance synaptic plasticity in CNS preparations. Furthermore, we proposed studies aimed at testing the hypothesis that structurally and functionally distinct allosteric activators of mGluR5 have efficacy in rodent models that predict antipsychotic activity and enhance multiple forms of cognitive function in rodent models.

In addition to evaluating mGluR5 PAMs in general, a major goal of the proposed studies was to determine whether mGluR5 PAMs that have different in vitro profiles (ie. pure PAMs versus ago-PAMs) behave in a similar manner in these studies or whether these compounds have different effects. If the latter is the case, In addition to evaluating mGluR5 PAMs in general, a major goal of the proposed studies was to determine whether mGluR5 PAMs that have different in vitro profiles (ie. pure PAMs versus ago-PAMs) behave in a similar manner in these studies or whether these compounds have different effects. If the latter is the case, this could have major implications in guiding the optimal profile of compounds that will ultimately advance to clinical development and would directly inform studies focused on optimization of clinical development candidates.

1. Conn, P.J., Lindsley, C.W. and Jones, C.K., 2009. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends in Pharmacological Sciences 30: 25-31.
2. Stauffer, S.R., 2011. Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5). ACS Chemical Neuroscience 2: 450-470.
3. Chen, Y., Goudet, C., Pin, J.-P. and Conn, P.J., 2008. N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) Acts through a Novel Site as a Positive Allosteric Modulator of Group 1 Metabotropic Glutamate Receptors. Molecular Pharmacology 73: 909-918.
4. Noetzel, M.J., Rook, J.M., Vinson, P.N., Cho, H., Days, E., Zhou, Y., Rodriguez, A.L., Lavreysen, H., Stauffer, S.R., Niswender, C.M., Xiang, Z., Daniels, J.S., Lindsley, C.W., Weaver, C.D. and Conn, P.J., 2011. Functional Impact of Allosteric Agonist Activity of Selective Positive Allosteric Modulators of mGlu5 in Regulating CNS Function. Molecular Pharmacology, in press.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 3
MLP Probe ML# for probe 1: ML254
PubChem Substance ID (SID) for probe 1: 125305189
PubChem Compound ID (CID) for probe 1: 53382545
Probe type for probe 1: Positive Allosteric Modulator
IC50/EC50 (nM) for probe 1: 8.7
Target for probe 1: mGlu5 PAM (gi: 8393490)
Disease relevance for probe 1: schizophrenia,
Anti-target for probe 1: mGlu1,2-4,6-8
Fold selectivity for probe 1: >800
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK143535/ (ID: 3036044)
Grant number for probe 1: MH062646
MLP Probe ML# for probe 2: ML273
PubChem Substance ID (SID) for probe 2: 125311644
PubChem Compound ID (CID) for probe 2: 53384845
Target for probe 2: mGluR5 (gi: 8393490)
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK143559/ (ID: 3036398)
Grant number for probe 2: MH062646
MLP Probe ML# for probe 3: ML332
PubChem Substance ID (SID) for probe 3: 144241527
PubChem Compound ID (CID) for probe 3: 60210882
Probe type for probe 3: PAM
IC50/EC50 (nM) for probe 3: 298
Target for probe 3: mGlu5 (gi: 8393490)
Disease relevance for probe 3: Schizophrenia
Anti-target for probe 3: mGlu1,2-4,6-8
Fold selectivity for probe 3: >800
NCBI Book chapter link for probe 3: http://www.ncbi.nlm.nih.gov/books/NBK154499/ (ID: 3050910)
Grant number for probe 3: MH062646
PubMed Publication ID (PMID) for probe 1: 24050755
PubMed Publication ID (PMID) for probe 2: 23140665
PubMed Publication ID (PMID) for probe 3: 23142615
NCBI Book chapter title for probe 1: Pure Positive Allosteric Modulators (PAMs) of mGlu5 with Competitive MPEP-Site Interaction
NCBI Book chapter title for probe 2: Identification of a Selective Allosteric Agonist of mGlu5
NCBI Book chapter title for probe 3: Identification of a glycine sulfonamide based non-MPEP site positive allosteric potentiator (PAM) of mGlu5
Additional Information
Grant Number: R01 MH062646

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