Orexin Receptor Antagonists: Historical Perspectives and Future Opportunities

Area of Science:

• Neuroscience and Pharmacology
• G protein-coupled receptors (GPCRs)
• Drug Discovery and Development

Background:

• Orexin receptors OX1 and OX2 are crucial for regulating sleep-wake cycles, feeding, reward, and energy balance.
• Since their deorphanization in 1998, over 200 patents for orexin receptor antagonists have been filed.
• Suvorexant (Belsomra®), a dual orexin receptor antagonist (DORA), was the first FDA-approved orexin antagonist in 2014 for insomnia treatment.

Purpose of the Study:

• To provide a historical perspective on the discovery and development of orexin receptor antagonists.
• To review dual orexin receptor antagonists (DORAs), selective OX1 receptor antagonists (1-SORAs), and selective OX2 receptor antagonists (2-SORAs).
• To consider future opportunities for orexin receptor antagonists in therapeutic applications.

Main Methods:

• Historical review of scientific literature and patent filings.
• Analysis of medicinal chemistry case studies for orexin receptor antagonists.
• Evaluation of clinical and pre-clinical data for DORAs, 1-SORAs, and 2-SORAs.

Main Results:

• DORAs, exemplified by suvorexant, are established treatments for insomnia.
• 2-SORAs are currently in clinical evaluation for their sleep-modulating effects.
• 1-SORAs have demonstrated potential in pre-clinical models for treating addiction.

Conclusions:

• Orexin receptor antagonists represent a significant advancement in neuroscience drug development.
• Different classes of orexin antagonists (DORAs, 1-SORAs, 2-SORAs) show diverse therapeutic potential.
• Continued research and development hold promise for novel orexin-targeted therapies.