Orexins are neuropeptides exclusively produced in the lateral hypothalamic areas. Orexin 1 receptor (OX1) and Orexin 2 receptor (OX2) are G-protein-coupled receptors that work together with orexins to regulate energy homeostasis, feeding and reward, and sleep-wake cycle. Almorexant is a dual OX1 and OX2 antagonist. It inhibited the binding of [125I]orexin-A to OX1 and OX2 overexpressed in CHO cells with IC50 values of 6.6 and 3.4nM, respectively. [3H]Almorexant binds to hOX1and hOX2 with Kd values of 1.3 and 0.17nM, respectively. Almorexant inhibited the binding of [3H]Almorexant to HEK293-hOX1 and -hOX2 cell membranes with Ki values of 4.7 and 0.9nM, respectively. Almorexant at 1μM antagonized orexin-A-induced increase of firing frequency of rat ventral tegmental area dopaminergic neurons[3]. The administration of Almorexant at 100mg/kg in a mouse binge-drinking model reduced ethanol intake compared to vehicle-treated controls. Almorexant at the doses of 50 and 100mg/kg also decreased the blood ethanol concentrations relative to the control mice[4].
Almorexant HCl/盐酸阿莫雷森特 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Grm2-Cre mice
Intraperitoneal injection
30 mg/kg
Single dose
Almorexant largely reversed the sleep fragmentation observed in LHb-TeLC mice, reducing wake time and increasing NREM sleep time, but had no significant effect on REM sleep time.
Curr Biol. 2018 Feb 19;28(4):580-587.e5
Wistar rats
Accelerating rotating rod (rotarod) and forepaw grip strength tests
Oral
30, 100, and 300 mg/kg
Single administration, testing lasted for 2.5 hours
To evaluate the effects of Almorexant alone or in combination with ethanol on motor performance. Results showed that Almorexant did not affect motor performance and did not further increase the sedative effects of ethanol when combined.
Neuropsychopharmacology. 2011 Mar;36(4):848-56
Mice
Wild-type and knockout mice
Oral
25, 50, 100, 200, 300 mg/kg
Single dose
Investigate the effects of Almorexant on sleep and locomotor activity
Sleep. 2012 Dec 1;35(12):1625-35
BALB/c mice
Unpredictable chronic mild stress (UCMS) model
Oral
100 mg/kg
Daily administration for 7 weeks
To investigate the antidepressant-like effects of almorexant on UCMS-induced behavioral and physiological alterations. Results showed that almorexant reversed UCMS-induced reductions in weight gain, increased aggression, increased despair behavior, and increased anxiety behavior. Additionally, almorexant restored UCMS-induced disruption of HPA axis negative feedback regulation but did not increase hippocampal cell proliferation and neurogenesis.
Neuropsychopharmacology. 2012 Sep;37(10):2210-21
Mice
Narcolepsy model
Intraperitoneal injection
30, 100, 300 mg/kg
Once every 3 days, lasting 12 hours
To evaluate the hypnotic and cataplexy-inducing efficacy of a Hcrt antagonist in an animal model with low Hcrt tone and compare the ALM efficacy profile in the disease model to that produced in wild-type (WT) control animals. Results showed that ALM exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/kg) paradoxically induced a transient increase in active wakefulness. Core body temperature (Tb) decreased after acute Hcrt receptor blockade, but the reduction in Tb that normally accompanies the wake-to-sleep transition was blunted in TG mice.
Sleep. 2013 Mar 1;36(3):325-36
Rats
Post-traumatic stress disorder (PTSD) animal model
Intraperitoneal injection
150 mg/kg
Single dose, observed for 7 days
Evaluate the effect of Almorexant on behavioral responses after PSS exposure, results showed that Almorexant increased the prevalence of PTSD phenotype.
Transl Psychiatry. 2020 Jan 21;10(1):10
Sprague-Dawley rats
Rats implanted for EEG/EMG recording
Oral
100 mg/kg
Single dose, observed for 90 minutes
To compare the effects of ALM and ZOL on the functional activation of wake-promoting systems at doses equipotent for sleep induction. Results showed that ALM is permissive for activation of Hcrt, HA, and ACh neurons during forced wakefulness, whereas ZOL inhibits activation of these cell groups.
Neuropsychopharmacology. 2016 Mar;41(4):1144-55
Mice
Wild-type mice and prepro-orexin knockout mice
Oral
30 and 100 mg/kg
Single administration, observed for 6 hours
To study the effects of Almorexant on sleep-wake behavior and cataplexy. Results showed that Almorexant dose-dependently increased NREM and REM sleep and increased cataplexy when combined with chocolate.
Sleep. 2020 Jun 15;43(6):zsz302
Mice
Kcna1 -null mice
Intraperitoneal injection
100 mg/kg
Once daily for 3 consecutive days
To evaluate the effects of Almorexant on sleep and seizures in Kcna1 -null mice. Results showed that Almorexant significantly increased the number and duration of NREM sleep epochs, reduced the latency to REM sleep onset, and decreased the incidence of severe seizures and overall seizure burden.
Sleep. 2016 Feb 1;39(2):357-68
Rats
Upper airway obstruction model
Oral gavage
300 mg/kg
Once daily for 8 days
To investigate the effect of Almorexant on sleep and growth plate morphology. Results showed that Almorexant significantly improved sleep and growth plate width in AO animals.
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