Peptide Basics
Orexin (Hypocretin): The Two Wakefulness Peptides, Their Receptors, Narcolepsy and the Medicines That Act on Them
Orexin, also called hypocretin, is a pair of neuropeptides, orexin-A and orexin-B, made by nerve cells in the hypothalamus that help keep the brain awake and take part in feeding; their loss is found in most people with narcolepsy. This page sets out how the two peptides are made and how they differ, their two receptors, what the narcolepsy research found, and the four medicines in FDA’s records that act on orexin receptors. Every figure is taken from UniProt, PubChem, MeSH, PubMed or FDA’s own databases and labels.
What orexin is
MeSH, the U.S. National Library of Medicine’s subject index, describes the orexins as neuropeptide hormones that regulate a variety of behavioural and physiological processes in response to motivational stimuli. UniProt is more specific: they play a significant role in regulating food intake and the balance of sleep and wakefulness, and a broader role in energy metabolism, the autonomic nervous system, hormonal balance and body fluids is suggested. MeSH files them among the neuropeptides.
The peptides have two names because two laboratories found them independently within weeks of each other. In January 1998 de Lecea and colleagues described a hypothalamus-specific precursor of two peptides they called hypocretins, noting a resemblance to the gut hormone secretin (PMID 9419374). In February 1998 Sakurai and colleagues described the same two peptides, called them orexin-A and orexin-B, identified their two receptors and showed that the peptides stimulate food consumption when given into the brain of rats (PMID 9491897).
The nerve cells that make them sit in one part of the brain. The discovery papers located them in the dorsal, lateral and posterior hypothalamus, and a 1999 paper describes orexin neurons as located exclusively in the lateral hypothalamus, sending fibres to many regions of the central nervous system, including the main centres that regulate sleep (PMID 10481909).
Sources: MeSH D000068797; UniProt O43612; PubMed 9419374, 9491897, 10481909. Read 10 November 2026.
Orexin-A and orexin-B: one precursor, two peptides
Both peptides are cut from a 131-amino-acid precursor, prepro-orexin, made by the HCRT gene. UniProt records that the cuts fall at pairs of basic amino acids, and maps the precursor like this:
| Piece | Positions | Amino acids | Note |
|---|---|---|---|
| Signal peptide | 1-33 | 33 | Steers the precursor out of the cell; removed first. |
| Orexin-A (hypocretin-1) | 34-66 | 33 | QPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL: a ring-closed first amino acid (pyroglutamate), an amide at the end and two disulfide bridges. |
| Orexin-B (hypocretin-2) | 70-97 | 28 | RSGPPGLQGRLQRLLQASGNHAAGILTM: a straight chain with an amide at the end and no disulfide bridges. |
| Propeptide | 98-131 | 34 | The tail of the precursor, removed in the mature form. |
The two peptides end in the same stretch, GNHAAGILT, followed by leucine in orexin-A and methionine in orexin-B. PubChem gives orexin-A the formula C152H243N47O44S4 and a molecular weight of 3,561.1 (CID 56842143), and orexin-B C123H212N44O35S and 2,899.3 (CID 44404987). The first 33 amino acids of the precursor are a signal sequence, explained on our signal peptides page.
Sources: UniProt O43612; PubChem CID 56842143 and 44404987. Read 10 November 2026.
The two orexin receptors, OX1R and OX2R
Both receptors are G protein-coupled receptors, and MeSH links them to appetite control and the sleep-wake cycle. They differ in what they prefer:
| Receptor (gene) | Amino acids | Binds | Note |
|---|---|---|---|
| OX1R (HCRTR1) | 425 | Orexin-A with high affinity, orexin-B with lower affinity | Signals through Gq and the phosphatidylinositol-calcium pathway; UniProt links it to food intake |
| OX2R (HCRTR2) | 444 | Both orexin-A and orexin-B | Can couple to Gq/11 or Gi/o; UniProt links it to the sleep-wake cycle. The receptor the 2026 narcolepsy medicine switches on |
Sources: UniProt O43613 (HCRTR1), O43614 (HCRTR2) and O43612; MeSH D064446. Read 10 November 2026.
Orexin and narcolepsy: what the research found
Narcolepsy is described by MeSH as recurrent daytime sleepiness and lapses in consciousness, frequently with cataplexy, sleep paralysis and hallucinations at sleep onset; UniProt describes cataplexy as a sudden loss of muscle tone triggered by emotions. The orexin link was established in a short run of papers, each indexed in PubMed:
- 1999: narcolepsy in dogs traced to a mutation in the orexin receptor 2 gene (PMID 10458611).
- 1999: mice without orexin found to show a pattern strikingly similar to human narcolepsy (PMID 10481909).
- 2000: orexin undetectable in the spinal fluid of seven of nine people with narcolepsy (PMID 10615891).
- 2000: a general loss of orexin in all six narcolepsy brains examined, with one orexin gene mutation in a single early-onset case among 74 patients screened (PMID 10973318).
- 2000: an 85 to 95 per cent reduction in the number of orexin neurons in people with narcolepsy (PMID 11055430).
UniProt now summarises the position: human narcolepsy is associated with a deficient orexin system, and orexins are absent or greatly diminished in the brain and spinal fluid of most narcoleptic patients. The Orzeyful label states that narcolepsy type 1, narcolepsy with cataplexy, is associated with the loss of orexin signalling. This section describes published records; it offers no advice on diagnosis or treatment.
Sources: MeSH D009290; UniProt O43612 (disease note); PubMed 10458611, 10481909, 10615891, 10973318, 11055430; Orzeyful U.S. label (2026). Read 10 November 2026.
Medicines that act on orexin receptors: what FDA’s records show
MeSH files orexin receptor antagonists as substances that bind to and block orexin receptors, used as sleep aids. The three insomnia labels describe the same idea: orexin A and orexin B are wake-promoting neuropeptides, and blocking them from OX1R and OX2R is thought to suppress wake drive. The fourth medicine, approved in 2026, works the other way round. The table lists each by the approval year recorded for its original application:
| Medicine | Application | Approved | What it does and what the label names it for |
|---|---|---|---|
| Belsomra (suvorexant) | NDA 204569 | 2014 | Blocks OX1R and OX2R. Labelled for insomnia with trouble falling or staying asleep. Contraindicated in narcolepsy. Schedule IV controlled substance. |
| Dayvigo (lemborexant) | NDA 212028 | 2019 | Blocks orexin receptors. Labelled for insomnia in adults. Contraindicated in narcolepsy. Schedule IV. |
| Quviviq (daridorexant) | NDA 214985 | 2022 | Blocks orexin receptors. Labelled for insomnia in adults. Contraindicated in narcolepsy. Schedule IV. |
| Orzeyful (oveporexton) | NDA 220860 | 2026 | The opposite action: switches OX2R on (an agonist). Labelled for narcolepsy type 1 (narcolepsy with cataplexy) in adults. Recorded as a new molecular entity with priority review and orphan status; the label says its controlled-substance schedule is still to be set by the DEA. |
The labels mirror each other: the blockers are contraindicated in narcolepsy, and the agonist is labelled for narcolepsy type 1, which its label associates with the loss of orexin signalling. None of the four is a peptide. PubChem gives suvorexant a weight of 450.9, lemborexant 410.4, daridorexant 450.9 and oveporexton 520.5, against 3,561.1 for orexin-A. Drugs@FDA also records a generic suvorexant application with tentative approval in December 2025 and no marketing status; the table shows the original application of each medicine and is not a list of every product.
Sources: Drugs@FDA via openFDA (original approval dates, data updated 6 November 2026); current U.S. labels for Belsomra, Dayvigo and Quviviq (indication, contraindication, mechanism, controlled-substance schedule) and the Orzeyful label published on Drugs@FDA; MeSH D000068796; PubChem CID 24965990, 56944144, 91801202 and 154617563. Read 10 November 2026. Doses are not reproduced here; the approved medicines that are themselves peptides are on our FDA-approved peptides page.
Medibact does not manufacture or sell peptides. We supply USP-grade bacteriostatic water, made in the USA, for research use only, and publish reference material like this page.
Where this sits in the rest of the reference
FAQ
What is orexin?
Orexin is the name of two neuropeptides, orexin-A and orexin-B, also called hypocretin-1 and hypocretin-2. Both are cut from one precursor made by the HCRT gene in nerve cells of the hypothalamus. UniProt describes them as playing a significant role in regulating food intake and sleep and wakefulness, and MeSH files them as neuropeptide hormones that regulate behaviour and body processes in response to motivational stimuli.
Why does orexin have two names?
Two laboratories found it independently and published within weeks of each other in 1998. De Lecea and colleagues called the peptides hypocretins and described them as hypothalamus-specific and similar to the gut hormone secretin (PNAS, January 1998). Sakurai and colleagues called them orexins and showed that they stimulate feeding in rats (Cell, February 1998). Both names are still used; UniProt lists the gene as HCRT and the peptides as orexin-A and orexin-B.
What is the difference between orexin-A and orexin-B?
Orexin-A has 33 amino acids, a ring-closed first amino acid and two internal disulfide bridges; orexin-B has 28 amino acids and is a straight chain. Both end in an amide. UniProt's receptor records state that OX1R binds orexin-A with high affinity and orexin-B with lower affinity, while OX2R binds both.
Where is orexin produced?
In nerve cells of the hypothalamus. The 1998 discovery papers located the peptides in neurons of the dorsal, lateral and posterior hypothalamus, and a 1999 paper describes orexin neurons as located exclusively in the lateral hypothalamus, with fibres reaching numerous regions throughout the central nervous system, including the main centres that regulate sleep.
What does orexin do?
Its best-documented roles are wakefulness and feeding. The FDA labels of the orexin-blocking insomnia medicines describe orexin A and orexin B as wake-promoting neuropeptides and state that the orexin signalling system plays a role in wakefulness. UniProt adds feeding, and suggests a broader role in energy metabolism, the autonomic nervous system, hormonal balance and body fluids.
What is the link between orexin and narcolepsy?
In 1999 two research groups showed that disrupting the orexin system causes narcolepsy in animals: dogs with a mutation in the orexin receptor 2 gene and mice lacking orexin. In 2000, studies of people with narcolepsy found orexin undetectable in the spinal fluid of seven of nine patients, a general loss of orexin in six narcolepsy brains, and 85 to 95 per cent fewer orexin neurons. UniProt now records that orexins are absent or greatly diminished in most narcoleptic patients. This page describes those records; it gives no advice on diagnosis or treatment.
Which medicines act on orexin receptors?
Drugs@FDA records three orexin receptor blockers for insomnia, suvorexant (Belsomra, 2014), lemborexant (Dayvigo, 2019) and daridorexant (Quviviq, 2022), and one medicine that does the opposite: oveporexton (Orzeyful, approved 5 August 2026), an orexin receptor 2 agonist labelled for narcolepsy type 1 in adults. The three insomnia medicines are contraindicated in narcolepsy, according to their labels.
Are the orexin medicines peptides?
No. PubChem gives suvorexant a molecular weight of 450.9, lemborexant 410.4, daridorexant 450.9 and oveporexton 520.5: small molecules. Orexin-A itself weighs 3,561.1 and orexin-B 2,899.3. The medicines are built to keep orexin off its receptors, or in oveporexton's case to switch one receptor on in its place.
Is this medical advice?
No. This page explains what orexin is, from public scientific and regulatory sources. It gives no dose, schedule or recommendation, and it does not discuss taking orexin or any product to change sleep or appetite; anyone treated with these medicines should follow their own clinician and product label. Peptides sold for research are labelled research use only, not for human use. Medibact supplies USP-grade bacteriostatic water, made in the USA, and is not affiliated with any manufacturer of the products named here.
References: UniProt O43612, O43613, O43614; MeSH D000068797, D064446, D000068796, D009290; PubChem CID 56842143, 44404987, 24965990, 56944144, 91801202, 154617563; PubMed 9419374, 9491897, 10458611, 10481909, 10615891, 10973318, 11055430; Drugs@FDA via openFDA and the current U.S. labels named above. Read 10 November 2026.
Educational use only — not medical advice. This guide summarizes information reported in published research and community practice for educational purposes. It is not medical advice and not a recommendation to use any compound. Any doses, schedules, or combinations shown are examples of what has been reported, not instructions for you. Many peptides described here are research compounds that are not FDA-approved for the uses discussed and may be investigational or restricted. Effects, risks, and legal status vary; individual needs and results vary. Consult a qualified, licensed healthcare professional before making any decision. Do not use this content to diagnose, treat, or dose yourself.