Christopher J. Winrow

Merck, USA

Abstract

[O19] In vivo characterization of novel dual orexin receptor antagonists

Orexin is a key neurotransmitter of central arousal and reward circuits in the CNS. Two receptors respond to orexin signaling, Orexin 1 Receptor (OX1R) and Orexin 2 Receptor (OX2R) with partially overlapping brain distributions. Genetic and pharmacological studies suggest orexin receptor antagonists could provide therapeutic benefit for insomnia and other disorders in which sleep/wake cycles are disrupted. A program was initiated within Merck Research Laboratories to develop a dual orexin receptor antagonist primarily aimed at alleviating insomnia.  The combination of robust and reproducible in vitro and in vivo assays has enabled an understanding of PK/PD relationships of our leads and rapidly driven development of small molecule orexin receptor antagonists. The implementation of this paradigm has been critical for validating the orexin receptors as viable targets for insomnia, and clinical indications beyond sleep disorders. This presentation will describe the sleep promoting effects of a series of small molecule OX1R and OX2R antagonists across preclinical species. Dual orexin antagonists effectively block orexin-induced locomotor activity, demonstrate receptor engagement in an ex vivo occupancy assay and promote sleep in multiple species. In addition to modulating sleep architecture, quantitative EEG analysis shows consistent and dose dependent effects of dual orexin receptor antagonists on low and high frequency spectral power. Unlike GABA modulators, orexin receptor antagonists modify sleep architecture by increasing deep sleep states at the expense of wakefulness. These findings importantly highlight the unique opportunity that an orexin antagonist might provide as a novel therapy for insomnia.

Keywords: orexin, sleep, antagonists, EEG

Biography

Christopher Winrow, PhD is a Director of Psychiatry Research in the Neuroscience Department at Merck & Co., Inc. in West Point, PA. Dr. Winrow received his BSc (Honors) in Molecular Biology from McMaster University and PhD in Cell Biology and Anatomy from the University of Alberta in Canada. He completed his Post-Doctoral Fellowship at the Salk Institute for Biological Studies in La Jolla, CA and joined the Neuroscience Department at Merck Research Laboratories in San Diego in 2002. His research focuses on the identification and development of novel therapies for insomnia, depression and other psychiatric indications.