HTL14242

Protein target name:

GRM5

Mechanism of action:

Negative Allosteric Modulator

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

GPCR

Subclass:

Metabatropic Glutamate Receptor

HUGO ID:

HGNC:4597

Entrez gene ID:

2915

UNIPROT ID:

P41594

Target alias:

mGlu5; GPRC1E; MGLUR5; PPP1R86

Probe Details

Chemical Probes Portal ID:

CPP2252

Probe alias:

51E, HTL0014242, cpd 25

PubChem CID:

86763358

ChEMBL ID:

CHEMBL3603923

SMILES string:

N#CC1=CC(C2=NC=NC(C3=NC=C(F)C=C3)=C2)=CC(Cl)=C1

InChi Key:

FQAXDSVNYVVQSE-UHFFFAOYSA-N

Orthogonal probe:

PF470

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO) δ: 8.02 (td, J = 8.7, 2.7 Hz, 1H), 8.29 (dd, J = 2.0, 1.4 Hz, 1H), 8.57–8.67 (m, 2H), 8.76 (t, J = 1.5 Hz, 1H), 8.84 (d, J = 2.7 Hz, 1H), 8.95 (d, J = 1.5 Hz, 1H), 9.44 (d, J = 1.2 Hz, 1H).

19F NMR (376 MHz, DMSO) δ: −125.85 (dd, J = 8.6, 4.6 Hz, 1F).

13C NMR (101 MHz,) δ: 113.1, 114.1, 117.1, 123.6 (d, 3JCF = 5.4 Hz, 1C), 124.6 (d, 2JCF = 19.2 Hz, 1C), 129.7, 131.5, 134.0, 134.9, 138.2 (d, 2JCF = 24.5 Hz, 1C), 139.0, 149.4 (d, 4JCF = 3.8 Hz, 1C), 158.9, 160.5 (d, 1JCF = 258.4 Hz, 1C), 160.8, 162.5.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

pKi

9.3

Potency assay:

[3H]-M-MPEP Binding Assay

PDB ID for probe-target interaction (3D structure):

5CGD

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

pIC50

9.2

Potency assay (cells):

IPone assay

Off target activity in cells

Probe Selectivity in Cell:

Cross-screened in an external panel (Eurofins) of 30 GPCR, kinase, ion-channel, and transporter targets, where the compound displayed at least 1000-fold selectivity against the panel members. HTL14242 was profiled in agonist, positive allosteric modulator (PAM), and antagonist/NAM modes against all eight mGlu receptors in an external screen (Euroscreen) displaying an excellent selectivity profile, with no appreciable receptor activation in agonist or PAM modes against any of the mGlu receptors. No appreciable inhibition was observed for mGlu1,2,4,6–8 in antagonist/NAM mode, with activity at the mGlu5 receptor (97% inhibition at 10 μM). A small degree of mGlu3 inhibition was noted (47% inhibition at 10 μM).

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

clean in HepG2 cytotoxicity assay, TC50 > 90 μM

In vivo validation

Organism:

Rat, Dog

Dose:

5, 10, 30 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

2.3 (R), 6.5 (D) h

Systemic clearance:

27 (R, D) mL/min/Kg

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.5b00892

Reference (PMID):

26225459

HTL14242

Probe Availability

Probe Information

Target Details

mGlu5; GPRC1E; MGLUR5; PPP1R86

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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HTL14242

Probe Availability

Probe Information

Target Details

mGlu5; GPRC1E; MGLUR5; PPP1R86

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?