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Published on: August 16, 2018
Discovery Of An Orexin Receptor Positive Potentiator
Jiyong Lee1, M Muralidhar Reddy1, Thomas Kodadek2
1Division of Translational Research, Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390 (USA).
Abstract:
The orexin neurohormones control a variety of important physiological processes by signaling through two related G protein-coupled receptors, including appetite and feeding, wakefulness and energy homeostasis. Pharmacological manipulation of orexin signaling is an important goal. Here we describe the isolation of orexin receptor ligands from a library of microarray-displayed peptoids via a novel two-color, cell-based screen. Functional analysis of derivatives of these "hits" resulted in the development of moderate potency, low molecular weight receptor antagonists. Moreover, further optimization efforts resulted in the fortuitous discovery of a compound that positively potentiates the activity of the receptor. This compound is the first small molecule reported to up-regulate orexin signaling.
Insights
Researchers identified novel small molecules targeting orexin receptors, which regulate crucial functions like wakefulness and appetite. They discovered both antagonists and a unique compound that enhances orexin signaling, opening new therapeutic avenues.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Orexin neurohormones are key regulators of physiological processes such as appetite, feeding, wakefulness, and energy homeostasis.
- Signaling occurs through two G protein-coupled receptors, making them targets for pharmacological intervention.
Purpose of the Study:
- To discover novel ligands for orexin receptors.
- To develop small molecule modulators of orexin signaling, including antagonists and potentiators.
Main Methods:
- Utilized a microarray-displayed peptoid library for ligand screening.
- Employed a novel two-color, cell-based assay for identifying orexin receptor ligands.
- Performed functional analysis and optimization of identified compounds.
Main Results:
- Isolated orexin receptor ligands from the peptoid library.
- Developed moderate potency, low molecular weight orexin receptor antagonists.
- Discovered a novel small molecule that positively potentiates orexin receptor activity.
Conclusions:
- The study successfully identified and optimized small molecules targeting orexin receptors.
- A unique small molecule potentiator of orexin signaling was discovered, representing a first-in-class compound.
- These findings offer new therapeutic strategies for conditions involving orexin system dysfunction.
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