ACT 335827

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Background

ACT 335827 is a potent and selective antagonist of OXR-1 with IC50 values of 120 and 2300 nM for OXR-1 and OXR-2, respectively [1].
Orexin receptor 1 (OXR-1) is a G-protein coupled receptor for neuropeptide orexin-A and regulates feeding behaviour. OXR-1 is expressed in the hypothalamus.
ACT 335827 is a potent and selective OXR-1 antagonist with Kb values of 41 and 560 nM for OXR-1 and OXR-2, respectively [1].
In the fear-potentiated startle rats, ACT-335827 (300 mg/kg) inhibited fear-induced startle reactions. Also, ACT-335827 (300 mg/kg) significantly reduced stress-induced tachycardia and hyperthermia. In the rat polydipsia model, ACT-335827 (300 mg/kg) inhibited compulsive drinking behavior [1]. In rats exposed to novelty stress, ACT-335827 (100 mg/kg) reduced the tachycardic and pressor by 48% and 32%, respectively [2]. In a diet-induced obesity(DIO) rat model, ACT-335827 increased the level of high-density lipoprotein and water intake. Also, it slightly increased body weight, which suggested that inhibition of OXR-1 had minimal impact in this model [3].

[1]. Steiner MA, Gatfield J, Brisbare-Roch C, et al. Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist. ChemMedChem, 2013, 8(6): 898-903.
[2]. Beig MI, Dampney BW, Carrive P. Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat. Neuropharmacology, 2015, 89: 146-156.
[3]. Steiner MA, Sciarretta C, Pasquali A, et al. The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome. Front Pharmacol, 2013, 4: 165.