Pharmacological characterization of MK-6096 – A dual orexin receptor antagonist for insomnia

@article{Winrow2012PharmacologicalCO,
  title={Pharmacological characterization of MK-6096 – A dual orexin receptor antagonist for insomnia},
  author={Christopher J Winrow and Anthony L Gotter and Christopher D. Cox and Pamela L. Tannenbaum and Susan L. Garson and Scott M. Doran and Michael J. Breslin and John D. Schreier and Steven V. Fox and Charles M. Harrell and Joanne Stevens and Duane R. Reiss and Donghui Cui and Paul J. Coleman and John J. Renger},
  journal={Neuropharmacology},
  year={2012},
  volume={62},
  pages={978-987}
}
Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
TLDR
The slow kinetics of the “dual” orexin receptor antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted, and raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.
Orexin (Hypocretin) Receptor Agonists and Antagonists for Treatment of Sleep Disorders
TLDR
The discovery of a critical role played by the orexin system in the regulation of sleep/wakefulness has opened the door of a new era for sleep medicine.
Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.
TLDR
From a structural perspective, this perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials.
Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone
TLDR
It is concluded that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either H CRTR alone.
Orexin OX2 Receptor Antagonists as Sleep Aids.
TLDR
The evidence that an OX2R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia is reviewed, with a view to finding the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep.
Orexin Receptor Antagonists
TLDR
It is proposed that REM sleep enhancement by DORAs may provide opportunities to treat specific neurological disorders and OX2R antagonists such as seltorexant may have broader applications as they appear to promote balanced sleep architecture in preclinical models and should, in theory, have a lower narcoleptic/cataplectic potential.
Effects of a newly developed potent orexin-2 receptor-selective antagonist, compound 1 m, on sleep/wakefulness states in mice
TLDR
Results suggest that an orexin-mediated suppression of REM sleep via potential activation of OX1Rs in the locus coeruleus may possibly contribute to the differential effects on sleep/wakefulness exerted by a DORA as compared to a 2-SORA.
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TLDR
Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats, dogs, and rhesus monkeys, highlighting a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.
Orexin receptors: pharmacology and therapeutic opportunities.
TLDR
As the orexin system mainly promotes arousal, these new compounds will likely improve insomnia without incurring many of the side effects encountered with current medications.
Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia.
TLDR
Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations, leading to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats
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Discovery of a dual (OX1R/OX2R) orexin receptor antagonist featuring a 1,4‐diazepane central constraint that blocks orexIn signaling in vivo is described.
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In rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX1 and OX2 receptors, and this results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.
In Vitro Characterization of T-Type Calcium Channel Antagonist TTA-A2 and In Vivo Effects on Arousal in Mice
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The discovery of the potent and selective T-type channel antagonist TTA-A2 has enabled us to study the in vivo effects of pharmacological T-channel inhibition on arousal in mice, and it will help to explore the validity of these channels as potential drug targets for sleep-related and other neurological diseases.
Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates
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Findings provide strong evidence for the effectiveness of intranasal orexin-A in alleviating cognitive deficits produced by loss of sleep.
Involvement of the Lateral Hypothalamic Peptide Orexin in Morphine Dependence and Withdrawal
TLDR
A role for the orexin system in molecular adaptations to morphine is supported, and dramatic differences in molecular responses among different populations of LH neurons are demonstrated.
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