Orexin A
Hypocretin-1
Overview
Orexin A (Hypocretin-1) is a 33-amino-acid neuropeptide produced exclusively by neurons in the lateral hypothalamus that plays a master regulatory role in wakefulness arousal feeding behavior and reward processing. Loss of orexin neurons is the primary cause of narcolepsy with cataplexy — one of the best-characterized neurological sleep disorders. Orexin receptor antagonists (suvorexant lemborexant) are FDA-approved sleep medications demonstrating the clinical significance of this system. Orexin replacement therapy is under active investigation for narcolepsy and other hypersomnia conditions and represents a frontier in sleep medicine.
Mechanism of Action
Orexin A acts through two G-protein-coupled receptors OX1R and OX2R distributed throughout wake-promoting brain regions including the locus coeruleus (norepinephrine) dorsal raphe (serotonin) tuberomammillary nucleus (histamine) and ventral tegmental area (dopamine). By activating these monoaminergic wake-promoting systems Orexin A stabilizes the arousal state and prevents inappropriate transitions into sleep. The orexin system acts as a flip-flop switch that maintains stable wakefulness or sleep states by mutually inhibiting competing circuits. Orexin also regulates appetite and metabolism through effects on the hypothalamic feeding centers and modulates the reward system making it relevant to addiction and compulsive behavior research. Intranasal administration can deliver orexin peptides to the brain bypassing the blood-brain barrier through olfactory and trigeminal pathways.
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Dosage Information
Typical Dose
Research compound — no established human therapeutic dosing
Frequency
N/A for therapeutic use
Administration
Intranasal (research) or intracerebroventricular (animal studies)
Notes
Orexin replacement for narcolepsy is in clinical trials. Intranasal delivery is being investigated as a non-invasive route to restore orexin signaling in narcolepsy patients.
Compound Data
Molecular Formula
C152H243N47O44S4
Molecular Weight
3561.10 g/mol
IUPAC Name
(4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[2-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S,3S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(1R,4S,7S,10S,13S,16R,21R,24S,31R)-7-(4-aminobutyl)-10-(3-amino-3-oxopropyl)-13-(3-carbamimidamidopropyl)-31-[[(2S)-3-carboxy-2-[[(2S)-1-[(2S)-4-methyl-2-[[(2S)-1-[(2S)-5-oxopyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-4-[(1R)-1-hydroxyethyl]-24-(hydroxymethyl)-3,6,9,12,15,23,26,32-octaoxo-18,19,28,29-tetrathia-2,5,8,11,14,22,25,33-octazabicyclo[14.10.7]tritriacontane-21-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-oxopentanoic acid
PubChem CID
56842143Potential Side Effects
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Quick Facts
- Administration
- Intranasal (research) or intracerebroventricular (animal studies)
- Typical Dose
- Research compound — no established human therapeutic dosing
- Frequency
- N/A for therapeutic use
- References
- 0 curated + 46 from PubMed
- Clinical Trials
- 47 registered
- Evidence Score
- 80.0 / 100