MK-1064 serves as a specific, orally effective OX2R antagonist, with a Ki of 0.5 nM and an IC50 of 18 nM, and is observed to facilitate sleep in live models, suggesting its potential for insomnia research[1].[3].
体内研究
Through OX2R targeting, MK-1064 (administered orally at 30 mg/kg) selectively enhances sleep in rodent models, specifically in Wild-type mice[2].
With a 5-day, oral regimen at 30 mg/kg, MK-1064 counteracts the struggle behavior in rats induced by prior CNO treatment[3].
Additionally, varying doses of MK-1064 (1-5 mg/kg, administered either intravenously or orally) demonstrate moderate oral bioavailability and clearance rates in species including rats, dogs, and rhesus monkeys[1].
MK-1064 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
RTg4510 transgenic mouse model
Oral gavage
30 mg/kg
Single dose, observed for 23 hours
To assess the sleep/wake response of rTg4510 mice to MK-1064, results showed MK-1064 significantly reduced wake time and increased NREM and total sleep time, with a more sustained effect in male rTg4510 mice
Br J Pharmacol. 2022 Jul;179(13):3403-3417
Mice
Stress-Alternatives Model (SAM)
Intracerebroventricular injection
0.3 nmol
Single administration
MK-1064 (Orx 2 receptor antagonist) reduced escape behavior, increased anxious and depressive behaviors, and elevated plasma corticosterone levels.
Neuropharmacology. 2018 Dec;143:79-94
Female rhesus monkeys
Actigraphy-based sleep parameters model
Oral
1, 3 or 10 mg/kg
Single administration, with continuous monitoring of sleep parameters
To evaluate the effect of MK-1064 on methamphetamine-induced sleep impairments, results showed that MK-1064 dose-dependently improved actigraphy-based sleep parameters.
Drug Alcohol Depend. 2024 Jun 1;259:111285
Mice, rats, dogs, and humans
Wild-type and OX2R knockout mice, Sprague-Dawley rats, beagle dogs
Evaluate the sleep-promoting effects of MK-1064 in various species, showing significant increases in NREM and REM sleep time
Sci Rep. 2016 Jun 3;6:27147
Rats
Acute and repeated restraint stress model
Oral
30 mg/kg
Once daily for five days
To evaluate the effect of MK-1064 on the HPA axis response to acute and repeated stress. Results showed that MK-1064 pretreatment reduced day 1 ACTH levels but did not further promote habituation on day 5, indicating that endogenous OX2R activity plays a role in acute stress but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5.
Neuroscience. 2017 Apr 21;348:313-323
Female Wistar rats
Adolescent intermittent ethanol exposure model
Oral gavage
10 mg/kg and 20 mg/kg
Single administration, testing started 60 minutes after administration
To test the effects of MK-1064 on sleep pathology and waking event-related oscillations. Results showed that MK-1064 hastened SWS onset and increased the number of SWS episodes, without increasing sleep fragmentation in AIE and controls. Additionally, MK-1064 increased waking ERO energy in delta, theta, and beta frequency bands.
搜索
