UCSF7447

Protein target name:

MTNR1A

Mechanism of action:

Inverse Agonist

Recommended Concentration for use in cells:

Up to 1 uM

Probe Information

Target and Probe Information

Target Details

Target class:

GPCR

Subclass:

Melatonin Receptor

HUGO ID:

HGNC:7463

Entrez gene ID:

4543

UNIPROT ID:

P48039

Target alias:

MT1, MEL-1A-R

Probe Details

Chemical Probes Portal ID:

CPP1875

Probe alias:

ZINC555417447

PubChem CID:

138993662

SMILES string:

Clc1ccc(CNc2cccc(-c3nc[nH]n3)c2)c(Br)c1

InChi Key:

QPTCYEYTAWEZNT-UHFFFAOYSA-N

Control compound:

ZINC37781618

Physico-chemical properties

Solubility - preferred solvent:

50% DMSO/50% Ethanol

Solubility - concentration:

13 mM

NMR:

1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.46 – 7.40 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 5.7 Hz, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.57 (t, J = 7.7 Hz, 2H), 4.32 (d, J = 5.9 Hz, 2H).

13C NMR (126 MHz, Chloroform-d) δ 148.8, 138.1, 132.6, 132.1, 130.9, 130.4, 129.9, 128.3, 123.5, 114.6, 113.7, 46.8.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

7.5 nM

Potency assay:

Radioligand Binding

Off target activity

Probe Selectivity in Vitro:

Screened for radioligand binding modulation of CNS GPCRs and toxic pharmacological off-targets at 10uM, no activity was observed.

In cell validation

On target activity in cells

Potency in cells:

EC50

41 nM

Potency assay (cells):

Glo cAMP assay

Off target activity in cells

Probe Selectivity in Cell:

Counter-screened against MTNR1B and was 53-fold selective for MTNR1A. Also screened against a panel of 318 GPCRs at 10uM. Secondary concentration-response assays of preliminary hits demonstrated no replicable off-target action.

In vivo validation

Organism:

Mouse

Dose:

30 ug

Route of delivery:

Subcutaneous

Plasma half life:

0.27 to 0.32 h

Organ of Interest

Organ (O):

Brain

Primary Reference

Reference (doi):

10.1038/s41586-020-2027-0

Reference (PMID):

32040955

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

ZINC555417447 is a brain penetrant, inverse agonist (partial 62% Emax) of the Melatonin MT1 receptor, with good selectivity over the related MT2 receptor (53-fold selective in human and 158-fold in mouse). Although it has a relatively short half-life in vivo (it is comparable to the half-life of melatonin), as an inverse agonist it demonstrates an opposing effect to the natural agonist melatonin in a mouse model of ‘jet-lag’ at low doses (0.03 mg/kg s.c.). Importantly, the compound’s effects in vivo are eliminated in a mouse MT1-knockout and enhanced in an MT2-knockout. Together, the data supports its use in both cells and in vivo mouse models to investigate the role of MT1. The structurally related MT2 agonist ZINC128734226 would a useful probe to use alongside ZINC555417447 in any cell or in vivo experiments.

May 19 2020 - 10:55am

Thorough characterization has been performed by trustworthy scientists; an inactive analog (ZINC37781618) and an analogous, active probe for the related MT2 receptor (ZINC128734226) were characterized in parallel and provide a set of valuable tools to interrogate melatonin receptor pharmacology.

Jul 30 2021 - 4:43pm

UCSF7447

Probe Information

Target Details

MT1, MEL-1A-R

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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UCSF7447

Probe Information

Target Details

MT1, MEL-1A-R

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?