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Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists
Takashi Nagahara1, Tsuyoshi Saitoh2, Noriki Kutsumura2
1Department of Medicinal Chemistry, School of Pharmacy, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Abstract:
Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 μM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4'-methoxy-N,N-dimethyl-3'-[N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl)sulfamoyl]-(1,1'-biphenyl)-3-carboxamide 26.
Insights
Researchers discovered a new compound that acts as a potent and selective agonist for the orexin receptor 2 (OX2R). This finding offers a promising avenue for developing mechanistic therapies for narcolepsy and related sleep disorders.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Orexins are neuropeptides crucial for regulating sleep-wake cycles.
- They exert their effects via two G-protein-coupled receptors: orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R).
- Genetic and pharmacological studies highlight the therapeutic potential of orexin receptor agonists, particularly for OX2R, in treating narcolepsy and catalepsy.
Purpose of the Study:
- To discover and characterize novel orexin receptor agonists.
- To identify a potent and selective agonist for OX2R for potential narcolepsy treatment.
Main Methods:
- Synthesis and pharmacological evaluation of novel chemical entities.
- Assay of G-protein-coupled receptor activity to determine potency (EC50) and selectivity.
Main Results:
- Discovery of compound 26, a novel orexin receptor agonist.
- Compound 26 exhibits high potency for OX2R with an EC50 of 0.023 μM.
- Compound 26 demonstrates significant selectivity for OX2R over OX1R, with an OX1R/OX2R EC50 ratio of 70.
Conclusions:
- Compound 26 represents a potent and OX2R-selective agonist.
- This discovery provides a promising lead compound for the development of new therapies targeting orexin receptor 2 for sleep disorders like narcolepsy.
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