Orexin

Chemical Identity

Orexin-A (Hypocretin-1)

Property	Value
Name	Orexin-A / Hypocretin-1
Source	Lateral hypothalamus
Sequence	PLPDCCRQKTCSCRLYELLHGGAHGLQPCSPCCGQQRRCFWGSRC
Length	33 amino acids
Disulfide Bonds	2 (Cys6-Cys10, Cys7-Cys14)
MW	3561.0 Da
PDB Structures	1R0G (NMR)

Orexin-B (Hypocretin-2)

Property	Value
Name	Orexin-B / Hypocretin-2
Sequence	ELTPAYILILNLDQVCGLFAYRWGGQPRGQGTRSGRRR
Length	28 amino acids
MW	2936.5 Da

Receptors

Receptor	Gene	Distribution	Primary Effects
OX1R (HCRTR1)	HCRTR1	Locus coeruleus, cortex, hypothalamus	Wakefulness, feeding, reward
OX2R (HCRTR2)	HCRTR2	Hypothalamus, thalamus, brainstem	Wakefulness, energy expenditure

Physiological Functions

Wakefulness Regulation

Lateral hypothalamus → Orexin-A/B release
    → OX1R/OX2R (brainstem, thalamus)
    → ↑ Activity of wake-promoting neurons
    → ↑ Histamine (tuberomammillary nucleus)
    → ↑ Norepinephrine (locus coeruleus)
    → ↑ Serotonin (dorsal raphe)
    → Wakefulness maintenance

Appetite and Energy

• Orexin-A: Potent appetite stimulant (satiety signal from gut → orexin activation)
• OX2R: Stimulates energy expenditure, thermogenesis
• Leptin inhibits orexin neurons; ghrelin stimulates them

Other Functions

• Reward: Orexin neurons activated by drugs of abuse
• Stress: Orexin release during stress
• Autonomic: Regulates sympathetic tone
• Sleep-wake transitions: Prevents inappropriate transitions

Narcolepsy

Pathogenesis

• Type 1 narcolepsy (with cataplexy): Autoimmune destruction of orexin neurons
  • 85-95% reduction in CSF orexin levels
  • HLA-DQB1*06:02 association (>95% of patients)
• Type 2 narcolepsy (without cataplexy): Partial orexin deficiency
  • 30-50% reduction in CSF orexin levels

Symptoms

• Excessive daytime sleepiness (EDS)
• Cataplexy (sudden muscle tone loss)
• Hypnagogic hallucinations
• Sleep paralysis
• Disrupted nocturnal sleep

Clinical Applications

Orexin Receptor Antagonists (DORAs)

Drug	Target	Indication	Approval
Suvorexant (Belsomra)	OX1R + OX2R	Insomnia	FDA 2014
Lemborexant (Dayvigo)	OX1R > OX2R	Insomnia	FDA 2019
Daridorexant (Quviviq)	OX1R + OX2R	Insomnia	FDA 2022
Tidorexant	OX1R + OX2R	Insomnia	FDA 2023

Narcolepsy Treatment

• Orexin replacement: Investigational (intranasal orexin-A)
• Orexin agonists: Theraventiporexant (Phase II)
• Wake-promoting agents: Modafinil, armodafinil (symptomatic)

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• Disulfide formation: Air oxidation or glutathione buffer
• Purification: RP-HPLC
• Characterization: Mass spectrometry, CD spectroscopy

References

1. Lin L, et al. “The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.” Cell 98:365-376, 1999. doi:10.1126/science.284.5417.1228
2. Sakurai T, et al. “Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors.” Cell 92:573-585, 1998.
3. Thannickal TC, et al. “Reduced number of hypocretin neurons in human narcolepsy.” Journal of Neuroscience 20:RC33, 2000.
4. Mieda M, et al. “Orexin neurons function in energy homeostasis.” Journal of Neuroscience 24:4440-4448, 2004.
5. Herring WJ, et al. “Suvorexant for insomnia.” New England Journal of Medicine 372:1231-1239, 2015.