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Distribution of histone deacetylases 1–11 in the rat brain
- R. Broide, J. Redwine, N. Aftahi, W. Young, F. Bloom, C. Winrow
- BiologyJournal of Molecular Neuroscience
This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examining the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.
Orexin receptors: pharmacology and therapeutic opportunities.
- T. Scammell, C. Winrow
- Biology, PsychologyAnnual Review of Pharmacology and Toxicology
- 10 February 2011
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.
International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology
- A. Gotter, A. Webber, P. Coleman, J. Renger, C. Winrow
- Biology, PsychologyPharmacological Reviews
- 1 July 2012
Combined genetic and pharmacological approaches indicate that orexin signaling may represent a confluence of sleep, feeding, and reward pathways and selective oX2 receptor antagonism takes advantage of these properties toward the development of novel insomnia therapeutics.
Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity
- C. Winrow, M. L. Hemming, D. M. Allen, G. B. Quistad, J. Casida, C. Barlow
- Biology, ChemistryNature Genetics
- 17 March 2003
These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of NTE without the requirement for Nte gain of function or aging.
Adult mouse brain gene expression patterns bear an embryologic imprint.
- Matthew A. Zapala, I. Hovatta, C. Barlow
- BiologyProceedings of the National Academy of Sciences…
- 19 July 2005
A gene expression-based brain map measuring gene expression patterns for 24 neural tissues covering the mouse central nervous system found that the adult brain bears a transcriptional "imprint" consistent with both embryological origins and classic evolutionary relationships.
Pharmacological characterization of MK-6096 – A dual orexin receptor antagonist for insomnia
Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors
The orexin (also known as hypocretin) G protein–coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human…
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…
- Christopher D. Cox, M. Breslin, P. Coleman
- Biology, ChemistryJournal of Medicinal Chemistry
- 21 June 2010
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.
Promotion of Sleep by Suvorexant—A Novel Dual Orexin Receptor Antagonist
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.
Ataxia telangiectasia mutated is essential during adult neurogenesis.
A role for ATM is defined during the process of neurogenesis, it is demonstrated that ATM is required for normal cell fate determination and neuronal survival both in vitro and in vivo, and it points to a mechanism for neuronal cell loss in progressive neurodegenerative diseases.