The purpose of this randomized, double-blind, placebo-controlled, 5-period crossover study is to assess the effect of single oral doses of MK-1064 on latency to persistent sleep (LPS) as measured by polysomnography (PSG) in healthy young male participants, and to evaluate the safety and tolerability of single oral doses of MK-1064 and MK-6096 in healthy young male participants. The primary efficacy hypothesis is that at least one dose of MK-1064 is superior to placebo in decreasing LPS in healthy male participants as assessed by PSG.

Start Date06 Nov 2009

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT02549014 / CompletedPhase 1

A Single Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of MK-1064

The purpose of this randomized, double-blind, placebo-controlled study is to evaluate the safety, pharmacokinetics and pharmacodynamics of rising, single oral doses MK-1064 in healthy, young, male participants. The primary pharmacokinetic hypothesis is that at least one dose of MK-1064 that is generally safe and well tolerated produces an average MK-1064 plasma concentration from 0 to 4 hours of ≥2.2 μM. Since this is an early Phase I assessment of MK-1064 in humans, the study protocol allows for modifications to the outlined dose, dosing regimen and/or clinical or laboratory procedures, if required to address study objectives and/or to ensure appropriate safety monitoring of participants.

Start Date06 Jul 2009

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with MK-1064

100 Translational Medicine associated with MK-1064

100 Patents (Medical) associated with MK-1064

Literatures (Medical) associated with MK-1064

01 Jul 2024·The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer’s Disease in 3xTg-AD Mice

Article

Author: He, Ye-Xin ; Cai, Hong-Yan ; Jiao, Juan-Juan ; Wu, Mei-Na ; Zhang, Jin-Nan ; Hu, Xiao-Hong ; Wang, Lei ; Li, Xin-Xin ; Wang, Zhao-Jun ; Yu, Kai-Yue

AbstractThe orexin system is closely related to the pathogenesis of Alzheimer’s disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid β (Aβ) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aβ deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aβ pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

01 Jun 2024·Drug and Alcohol Dependence

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms

Article

Author: Borgatti, Daniel A ; Rowlett, James K ; Berro, Lais F

BACKGROUNDThe orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys.METHODSActigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4).RESULTSMethamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep.CONCLUSIONSThese findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

01 Jan 2024·British Journal of Pharmacology

Orexin 2 receptor antagonism sex‐dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice

Article

Author: Barnham, Kevin J ; Hoyer, Daniel ; Wright, David K ; Jacobson, Laura H ; Clarke, Kyra ; Keenan, Ryan J ; Stephenson, Sarah ; Cornthwaite-Duncan, Linda ; Oberrauch, Sara ; Nowell, Cameron J ; Allocca, Giancarlo ; Brian, Maddison ; Metha, Jeremy ; Daykin, Heather

AbstractBackground and PurposeTau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown.Experimental approachThree 8‐week experiments were conducted with wild‐type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg−1·day−1); or (3) Active phase non‐NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX2) receptor antagonist MK‐1064 (40 mg·kg−1·day−1). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry.Key ResultsTau transgene suppression improved tauopathy and hippocampal‐dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX2 receptor antagonism induced only short‐lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau‐ and sex‐dependent disruption of OX2 receptor signalling.Conclusions and ImplicationsPharmacologically reducing hyperarousal corrects tau‐induced sleep/wake and cognitive deficits. Tauopathy causes sex‐dependent disruptions of OX2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.

100 Deals associated with MK-1064

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