Uses
ACT 335827 is an orally available, brain penetrant orexin receptor type 1 selective antagonist and elicits anxiolytic-like effects without promoting sleep.
Biological Activity
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].
Enzyme inhibitor
This brain-penetrant and orally available orexin receptor antagonist (FW = 518.64 g/mol; CAS 1354039-86-3; Soluble to 100 mM in DMSO, also known as (aR,1S)-1-[(3,4-Dimethoxyphenyl)methyl]-3,4-dihydro-6,7dimethoxy-N-(1-methylethyl)-a-phenyl-2(1H)-isoquinoline acetamide, elicits its anxiolytic effects in vivo by targeting OX1 (Ki = 41 nM) and OX2 (Ki = 560 nM) receptors. ACT-335827 decreases fear, compulsive behaviors, and autonomic stress reactions in rats.
in vivo
ACT-335827 (oral gavage, 30-100 mg/kg, once) can reduce the fear-induced startle response with no affecting motor or cognitive function in rats[1].
ACT-335827 (oral administration, 300 mg/kg, everyday, 4 weeks) has less effect on metabolic syndrome (MetS), such as diet-induced obesity (DIO) in male Wistar rats[2].
| Animal Model: | Rats[1] |
| Dosage: | 30, 100 or 300 mg/kg |
| Administration: | Oral gavage; once |
| Result: | Reduced fear-induced startle response at 300 mg/kg.
Decreased stress-induced elevated body temperature at 300 mg/kg and accelerated heat rate at 100 or 300 mg/kg but no effect on locomotion and blood pressure.
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| Animal Model: | Male Wistar rats weighing160-180g[2] |
| Dosage: | 300 mg/kg |
| Administration: | Oral administration; everyday; 4 weeks |
| Result: | Reduced preference for high fat/sweet diets but no effect on absolute energy intake.
Increased water intake and HDL relative to total cholesterol.
Resulted in a 4% weight gain compared to the control group.
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IC 50
OX1: 6 nM (IC50); OX2: 417 nM (IC50)
References
[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.
