1. Discovery of a Potent, CNS-Penetrant Orexin Receptor Antagonist Based on anN,N-Disubstituted-1,4-diazepane Scaffold that Promotes Sleep in Rats
- Author
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John J. Renger, Chunze Li, Michael J. Bogusky, Yuxing Li, Scott M. Doran, David B. Whitman, Wei Lemaire, John D. Schreier, Joseph G. Bruno, Karen M. Brashear, Duane R. Reiss, Thomayant Prueksaritanont, Rodney A. Bednar, C. Meacham Harrell, Susan L. Garson, Paul J. Coleman, Richard L. Kraus, Christopher D. Cox, George D. Hartman, Kenneth S. Koblan, Michael J. Breslin, and Christopher J. Winrow
- Subjects
Central Nervous System ,Receptors, Neuropeptide ,Sleep Wake Disorders ,medicine.medical_specialty ,Pharmacology ,Biochemistry ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,Orexin Receptors ,In vivo ,Oral administration ,Internal medicine ,mental disorders ,Drug Discovery ,medicine ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Chemistry ,digestive, oral, and skin physiology ,Organic Chemistry ,Antagonist ,Azepines ,Sleep in non-human animals ,Orexin receptor ,Rats ,Orexin ,Endocrinology ,nervous system ,Molecular Medicine ,Wakefulness ,Antagonism ,psychological phenomena and processes - Abstract
Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
- Published
- 2009
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