note: The Chemical Probes Portal only endorses
compounds as chemical probes for use as specific and
selective modulators of the proposed target if they
receive three or more (3-4) stars.
Potency assay (off target):
More than 700-fold OX2R selectivity over OX1R (calcium mobilization using hOX1R/CHO-K1 cells was 14,000 nM). The inhibitory or stimulatory activities of TAK-994 against various enzymes, receptors, and ion channels (106 targets in total) were assessed. TAK-994 at 10 μM did not induce more than 50% inhibition or stimulation of any enzymes, receptors, and ion channels, except progesterone receptor B (55% inhibition), indicating high selectivity of TAK-994 for OX2R with minimal off-target activity in vitro
Potency assay, off target (cells):
Selectivity vs hOX1R was assessed in CHO-K1 cells showing EC50 14000 nM
There are many compounds indexed against this target in ChEMBL https://www.ebi.ac.uk/chembl/g/#browse/activities/filter/target_chembl_id%3ACHEMBL4792%20AND%20standard_type%3A(%22IC50%22) These can be inspected for low-activity contro compounds and orthogonal probes.
The PubChem entry for this compound is https://pubchem.ncbi.nlm.nih.gov/compound/137460733
(last updated:
27 Aug 2023 )
SERP
Ratings
In Cell Rating
In Model Organisms
SERP
Comments:
An exceptionally well characterized probe compound, with demonstrated in vivo (po in mouse) and in cell pharmacology and pharmacodynamic activity. Orally bioavailable, cell-permeable and brain penetrant.
(last updated:
27 Aug 2023 )
SERP+
Ratings
In Cell Rating
In Model Organisms
SERP+
Comments:
TAK-994 is a potent OX2R full agonist (KD = 85 nM) with good selectivity against OX1R (>700-fold). TAK-994 (10 μM single dose) was tested against a panel of >100 enzymes, receptors, and ion channels; of these, only OP1 (33%) and PR-B (55%) showed significant inhibition. TAK-994 shows dose-dependent induction of downstream OX2R signalling, including IP1 synthesis, β-arrestin recruitment, phosphorylation of ERK1/2 and CREB, and membrane depolarization. I highly recommend TAK-994 as an in vitro chemical probe against OX2R. In vivo PK data is available against mice and monkeys, with TAK-994 significantly increasing wakefulness in mouse and monkey narcolepsy models. This suggests sufficient CNS brain penetration, although quantitative brain penetration data is unavailable. I recommend TAK-994 as an in vivo chemical probe; however, its short residence time (~30 min in both mice and monkeys) should be considered.
