ACT 462206

ACT-462206 is an orally active and potent dual Orexin 1/Orexin 2 receptor antagonist with IC50s of 60 nM (Orexin 1) and 11 nM (Orexin 2), respectively. ACT-462206 exhibits brain penetration properties, and can be used for insomnia, stress/anxiety-related disorders and addiction research[1].

Research Areas >> Others

Signaling Pathways >> GPCR/G Protein >> Orexin Receptor (OX Receptor)

OX2

OX1

Orexins are released in a Ca2+-sensitive manner at axonal terminals and can then bind to two closely related G-protein-coupled receptors (GPCRs): orexin receptor type 1 (OX1) and orexin receptor type 2 (OX2)[1]. ACT-462206 shows binding affinity with Kbs of 17 nM (hOX1), 2.4 nM (hOX2), 28 nM (rOX1), 9.9 nM (rOX2), 27 nM (dOX1), 4.2 nM (dOX2), respectively[1]. ACT-462206 inhibits Orexin activity with IC50s of 60 nM (hOX1), 11 nM (hOX2), 48 nM (rOX1), 9.6 nM (rOX2), 68 nM (dOX1), 26 nM (dOX2), respectively[1]. ACT-462206 inhibits CYP450 3A4T and 3A4M with IC50s of 15 μM and 29 μM, respectively[1].

ACT-462206 (compound 24) (100 mg/kg; p.o.; sampling at 3 h) can go cross blood brain barrier, with concentrations are 2267 ng/mL and 1219 ng/g in plasma and brain, respectively in male Wistar rats[1]. ACT-462206 (10-300 mg/kg; p.o.; single dose) shows sleep-promoting effects in male Wistar rats and in male Beagle dogs, with decreasing wakefulness and increasing non-rapid eye movement (non-REM) and REM sleep[1]. ACT-462206 (100, 300 mg/kg; p.o.; single dose) exerts anxiolytic-like effects, decreases the fear-potentiated startle reflexes in response to a sudden loud noise in rats, reduces the socialstress-induced increases of locomotion, body temperature, and heart rate[1]. Pharmacokinetics in different species[1] Route Dose (mg/kg) AUC (ng•h/mL) CL (mL/min/kg) Vss (L/kg) t1/2 (h) cmax (ng/mL) tmax (h) F1/2 (%) rat i.v. 1 586 29 1.8 1.9 / / / p.o. 10 2310 / / / 1600 0.5 39 dog i.v. 1 1490 11 1.4 1.7 / / / p.o. 3 2750 / / / 426 0.5 52 Animal Model: Male Wistar rats[1] Dosage: 0, 10, 30, 100, 300 mg/kg Administration: Oral gavage; single dose Result: Decreased the latency to the first persistent episode of non-REM sleep (60 s) and the first persistent episode of REM sleep (30 s). Dose-dependently decreased total wake time and behavioral home cage activity (one-way ANOVA; p <0.001), while increasing REM and non-REM sleep times.

[1]. Boss C, et al. Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist. ChemMedChem. 2014 Nov;9(11):2486-96.