UCSF4226

Protein target name:

MTNR1B

Mechanism of action:

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:7464

Entrez gene ID:

4544

UNIPROT ID:

P49286

Target alias:

MT2, FGQTL2, MEL-1B-R

Probe Details

Chemical Probes Portal ID:

CPP1872

Probe alias:

ZINC128734226

PubChem CID:

103828029

SMILES string:

COC1=CC(=C(C=C1)Br)CNC2=CN=CC=C2

InChi Key:

BLNNXJOEJRKHAM-UHFFFAOYSA-N

Control compound:

ZINC1848444290

Physico-chemical properties

Solubility - preferred solvent:

Ethanol

Solubility - concentration:

13 mM

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

63 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

7.1 nM

Potency assay (cells):

Glo cAMP assay

Off target activity in cells

Probe Selectivity in Cell:

Counter-screened against MTNR1A and was >54-fold selective for MTNR1B. 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

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

Outstanding characterisation of this probe. I recommend its use in animals and in cells to selectively modulate MT activity.

Jun 2 2020 - 4:50pm

This is clearly a good probe candidate but from a single publication so far. The two melatonic receptor human paralogues are well studied pharmacologically so additional compounds and controls are also available for comparative testing.

Jun 7 2020 - 11:21am

UCSF4226 is a high affinity brain-penetrant inverse agonist of melatonin receptor MTNR1B (MT2). Sufficient selectivity against GPCR target family and common off-targets has been demonstrated. Cellular activity was demonstrated in HEK293 and CHO cell lines. The selectivity for MT2 over MT1 was demonstrated in vitro for the human receptor only, the selectivity was lost for the mouse receptor and was not assessed in other species. In vivo pharmacology evaluation has not been performed.

Sep 24 2020 - 11:14am

UCSF4226

Probe Information

Target Details

MT2, FGQTL2, MEL-1B-R

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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UCSF4226

Probe Information

Target Details

MT2, FGQTL2, MEL-1B-R

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?