Identification of Highly Selective Orexin 1 Receptor Antagonists Driven by Structure-Based Design

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Orexin receptor 1 (OX1) antagonists show therapeutic potential for substance abuse, personality, eating, and anxiety disorders.
• Existing dual OX1/OX2 receptor antagonists cause undesirable sleepiness, limiting their clinical use.
• A need exists for OX1-selective antagonists with a safe therapeutic window, avoiding OX2-mediated side effects.

Purpose of the Study:

• To design and identify highly selective OX1 receptor antagonists.
• To overcome the limitations of dual OX1/OX2 receptor antagonists by achieving OX1 selectivity.
• To develop novel compounds with potential therapeutic applications in various neurological and psychiatric disorders.

Main Methods:

• Structure-based drug design utilizing the X-ray crystal structure of the OX1 receptor bound to suvorexant.
• Modification of a moderately selective [2.2.1]-bicyclic scaffold based on binding mode hypotheses.
• Synthesis and hit-to-lead evaluation of novel OX1 receptor-selective compounds.

Main Results:

• A novel series of OX1 receptor-selective antagonists was designed and synthesized.
• Structural modifications led to a modified core scaffold with enhanced inherent selectivity for OX1 over OX2.
• The developed compounds demonstrate potential as selective OX1 antagonists with an improved safety profile.

Conclusions:

• Structure-based design effectively yielded highly selective OX1 receptor antagonists.
• The novel scaffold offers a promising starting point for developing therapeutics for OX1-related conditions.
• This work provides a foundation for future drug discovery targeting the orexin system.