Orexin-B Research

Orexin-B, also called hypocretin-2, is a 28-residue neuropeptide first described in the hypothalamus. Orexin-B research is a small literature. A live PubMed count on 2026-08-28 returned 81 records with orexin-B in the title, against 868 for orexin-A. Many of the 81 orexin-B title records are tissue-localization and reproductive-tissue studies, concentrated in pigs and extending to species such as gecko, tilapia and piranha. The mammalian central pharmacology base is smaller again. Most popular orexin knowledge comes from the orexin-A work, and it is not evidence about orexin-B.

What orexin-B is

Sakurai and colleagues described both orexins in 1998, as two peptides cleaved from one precursor and activating the receptors OX1R and OX2R ^[1]. In that origin study, central administration of either peptide increased food consumption in rats ^[1].

The two are not variants of one another. Orexin-B is a linear 28-residue peptide with an amidated C terminus and no disulfide bonds. Orexin-A is 33 residues, blocked at its N terminus and held by two internal disulfide bonds. Solution NMR of human orexin-B shows two alpha helices joined by a short linker ^[2].

Two different CAS registry numbers circulate for this one molecule in public compound databases, so two spec sheets can describe the same 28-mer. "Oroxin B" is an unrelated plant flavonoid glycoside, separated from Orexin-B by a single substituted letter.

Receptor profile: preferring, not selective

Orexin-B is widely called OX2R-selective, but the primary data support a preference rather than selectivity. The affinity figures usually quoted, roughly 36 nM at OX2R against roughly 420 nM at OX1R, trace to Sakurai 1998 and amount to roughly a ten to twelve-fold preference ^[1]. Those figures do not appear in the paper's abstract. The IUPHAR Guide to Pharmacology lists orexin-B as a full agonist at both receptors, with overlapping potency ranges.

Genuine OX2R selectivity in a peptide required engineering. Asahi and colleagues made [Ala11, D-Leu15]orexin-B and reported roughly 400-fold OX2R selectivity in cell assays ^[3]. Lang and colleagues later produced truncated analogues exceeding 1000-fold selectivity in vitro ^[4]. Those are designed molecules, and their selectivity data do not describe the parent peptide.

The result that anchors orexin-B research

Kastin and Akerstrom compared the two peptides in mice ^[5]. Radiolabeled orexin-A entered the brain rapidly from blood by simple diffusion and reached brain tissue intact ^[5]. Orexin-B was rapidly degraded in blood, and no intact labeled orexin-B was detectable in brain after peripheral injection ^[5]. It was also far less lipophilic, by roughly eight-fold on the octanol/buffer partition coefficient ^[5]. This is a mouse result. A sheep study tested food intake after intravenous delivery of porcine orexin-B rather than brain entry ^[7].

The in vivo record fits that constraint. Among positive orexin-B results in animals with a stated route, all but one used delivery directly into the brain.

The literature does contain one peripheral-route positive. Dyer and colleagues gave synthetic porcine orexin-B by intramuscular injection to 26 weanling piglets ^[6]. Treated pigs ate an additional meal at 12 hours, and total 24-hour feed intake improved by 18 percent ^[6]. The intramuscular exposure per unit body weight was about a thousand times the intravenous exposure that did nothing in sheep ^[6][7]. The study reported no mechanism and demonstrated no central access. It is a single agricultural study from 1999 with no replication.

Sartin and colleagues found that intravenous porcine orexin-B had no effect on food intake, metabolites or hormone concentrations in sheep, while central delivery raised feed intake ^[7]. Central delivery also raised plasma cortisol in those sheep ^[7].

Where orexin-A is active and orexin-B is not

Four side-by-side studies returned a signal for orexin-A and none for orexin-B:

• Brain entry from blood in mice, where orexin-A crossed and orexin-B did not ^[5].
• Arousal in neonatal chicks, where central orexin-A raised arousal in layer-type birds while central orexin-B altered neither arousal nor food intake in either stock tested ^[8].
• Metabolism in isolated porcine adipocytes, where orexin-A altered lipid metabolism and leptin secretion and orexin-B did not ^[9].
• Plasma concentrations in human obesity, where orexin-A was lower in obese women and orexin-B did not differ between groups ^[10]. That study was observational, in 36 obese and 16 lean women.

The chick result matters for a common inference: the approved orexin antagonists are insomnia drugs, which invites the reasoning that an orexin agonist must promote wakefulness. Orexin-B's own arousal test was negative ^[8].

Preclinical orexin-B findings

Orexin-B is not a diluted orexin-A. In rat midbrain cultures where dopamine neurons die spontaneously, orexin-B gave partial but significant protection, while orexin-A had only marginal effects ^[11]. An OX2R antagonist abolished the protection and an engineered OX2R-selective analogue reproduced it ^[11]. This is cell culture.

Two groups report the same direction in rodent MPTP parkinsonian models. Bian and colleagues found that intracerebroventricular orexin-B excited nigral dopaminergic neurons through OX2R and improved motor measures in mice ^[12]. Ma and colleagues reported reduced dopamine neuron loss in MPTP mice and reduced MPP+ toxicity in SH-SY5Y cells ^[13]. The route of orexin-B delivery in that animal arm is not stated in the abstract. Neither report has been replicated in a third laboratory.

The same peptide also kills cells, through the receptor it prefers less. Nicole and colleagues used alanine scanning in cells expressing OX1R to map the orexin-B residues driving OX1R-mediated apoptosis ^[14]. That group had earlier reported orexin-induced apoptosis in colon cancer lines ^[14]. This is receptor-mediated pharmacology of the peptide in vitro, not an incidental toxicity.

In rat brain slices, orexin-B depressed glutamatergic input to dorsal raphe serotonin neurons through retrograde endocannabinoid signaling, which the authors call surprising for a wake-promoting peptide ^[15]. In isolated neonatal rat brainstem-spinal cord preparations, orexin-B antagonized respiratory depression induced by sevoflurane, propofol and remifentanil ^[16]. Sevoflurane reversal required the higher of two concentrations tested, while propofol and the lower remifentanil concentration were antagonized at the lower one ^[16].

Rotondo and colleagues found by circular dichroism that orexin-B is unordered in water and helical only in membrane-mimetic media ^[17]. Oxidative conditions oxidized its C-terminal methionine, a residue the alanine scan flagged as binding-critical ^[14][17]. Deamidation at the Asn-His site was a second degradation route in that work ^[17].

Human research and regulatory status

No person has received orexin-B in a registered trial. A live ClinicalTrials.gov check on 2026-08-28 returned no study in which orexin-B or hypocretin-2 is the intervention. Term searches on that registry return hits such as orexin-antagonist trials and observational studies of endogenous orexin levels, not the peptide. There is no human pharmacokinetic, safety or dose-finding data for this peptide.

Orexin-B is not an approved drug in the United States. Drugs@FDA queries by active ingredient and by brand name return no application of any kind for orexin or for hypocretin. This is a never-filed status rather than a withdrawal or a refusal.

Three approved insomnia drugs act at these receptors in the opposite direction. Suvorexant (NDA204569), lemborexant (NDA212028) and daridorexant (NDA214985) are orexin receptor antagonists. They block the receptors orexin-B activates, so their trial data are evidence about antagonism. Almorexant, a fourth orexin receptor antagonist, reached phase 3 in chronic insomnia, holds no United States approval of any kind, and its development was discontinued.

The agonist direction now has a human record, and it belongs to small molecules rather than to the peptide. TAK-994, an oral OX2R agonist, had its phase 2 narcolepsy trial and extension stopped early for hepatic adverse events, leaving primary endpoint data for 41 of 73 randomized patients ^[18]. A different molecule from the same sponsor went further. Oveporexton, the international nonproprietary name for TAK-861, holds a live FDA approval under NDA220860 for narcolepsy type 1 ^[19]. Danavorexton, another OX2R agonist, has completed randomized phase 1 work in healthy men ^[20]. The danavorexton trial reported more treatment-emergent adverse events on drug than on placebo, all rated mild, and one drug-related case of insomnia ^[20]. These are small molecules of different chemistry, and none of their results is orexin-B evidence in either direction. Other companies have OX2R agonist programs in ongoing trials, and none of those molecules is the peptide either.

Commercial interests run through the agonist literature: Takeda sponsored the TAK-994 trial and develops oveporexton and danavorexton ^[18][19][20]. The engineered OX2R-selective analogue came from Banyu Pharmaceutical, then the Japanese affiliate of Merck & Co ^[3]. The affinity figures most often copied into product descriptions reach PubChem through a commercial peptide supplier's depositor comment. The primary source for those figures is Sakurai 1998 ^[1].

Conclusion

The orexin-B record is short. It is an OX2R-preferring full agonist at both orexin receptors, and it does not reach the brain intact from the bloodstream in mice. Four side-by-side studies returned a signal for orexin-A and none for orexin-B. Its positive findings sit in cell culture and in animals. Among positive orexin-B results in animals with a stated route, all but one used delivery directly into the brain. Two groups agree on the direction in rodent MPTP models, and neither report has been repeated in a third laboratory. One 1999 pig study reported a feeding effect by a peripheral route, and it stands alone ^[6]. Orexin-B has never been administered to a human being in a registered study.

Frequently Asked Questions

Has orexin-B ever been given to people? No person has received orexin-B in a registered trial, on a live ClinicalTrials.gov check dated 2026-08-28. There is no human pharmacokinetic, safety or dose-finding data for this peptide. The human study cited here separating the two peptides was observational, and it measured plasma concentrations rather than testing administration ^[10].

Is orexin-B OX2R-selective? The primary data support a preference rather than selectivity. The quoted affinities are roughly 36 nM at OX2R against roughly 420 nM at OX1R, roughly a ten to twelve-fold preference, traced to Sakurai 1998 ^[1]. The IUPHAR Guide to Pharmacology lists orexin-B as a full agonist at both receptors. The genuinely OX2R-selective peptides are engineered analogues, not orexin-B ^[3][4].

Do the approved orexin drugs tell you anything about orexin-B? Suvorexant, lemborexant and daridorexant are orexin receptor antagonists approved for insomnia, and they block the receptors orexin-B activates. Their trial data are evidence about antagonism. An OX2R agonist is now approved for narcolepsy type 1, oveporexton under NDA220860, but it is a small molecule and not the peptide ^[19].

Are orexin-A findings transferable to orexin-B? Four side-by-side studies returned a signal for orexin-A and none for orexin-B. Those were brain entry from blood in mice ^[5], arousal in neonatal chicks ^[8], adipocyte metabolism in pigs ^[9], and plasma concentrations in human obesity ^[10]. The human one was observational, and it measured plasma concentrations rather than testing administration ^[10]. In rat midbrain culture orexin-B protected dopamine neurons where orexin-A had only marginal effects ^[11].

References

1. 1

   Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573-85. PMID 9491897
2. 2

   Lee JH, Bang E, Chae KJ, Kim JY, Lee DW, Lee W. Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B. Eur J Biochem. 1999;266(3):831-9. PMID 10583376
3. 3

   Asahi S, Egashira S, Matsuda M, Iwaasa H, Kanatani A, Ohkubo M, Ihara M, Morishima H. Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B. Bioorg Med Chem Lett. 2003;13(1):111-3. PMID 12467628
4. 4

   Lang M, Söll RM, Dürrenberger F, Dautzenberg FM, Beck-Sickinger AG. Structure-activity studies of orexin A and orexin B at the human orexin 1 and orexin 2 receptors led to orexin 2 receptor selective and orexin 1 receptor preferring ligands. J Med Chem. 2004;47(5):1153-60. PMID 14971895
5. 5

   Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J Pharmacol Exp Ther. 1999;289(1):219-23. PMID 10087007
6. 6

   Dyer CJ, Touchette KJ, Carroll JA, Allee GL, Matteri RL. Cloning of porcine prepro-orexin cDNA and effects of an intramuscular injection of synthetic porcine orexin-B on feed intake in young pigs. Domest Anim Endocrinol. 1999;16(3):145-8. PMID 10343916
7. 7

   Sartin JL, Dyer C, Matteri R, Buxton D, Buonomo F, Shores M, Baker J, Osborne JA, Braden T, Steele B. Effect of intracerebroventricular orexin-B on food intake in sheep. J Anim Sci. 2001;79(6):1573-7. PMID 11424696
8. 8

   Katayama S, Hamasu K, Shigemi K, Cline MA, Furuse M. Intracerebroventricular injection of orexin-A, but not orexin-B, induces arousal of layer-type neonatal chicks. Comp Biochem Physiol A Mol Integr Physiol. 2010;157(2):132-5. PMID 20595012
9. 9

   Pruszynska-Oszmalek E, Kolodziejski PA, Kaczmarek P, Sassek M, Szczepankiewicz D, Mikula R, Nowak KW. Orexin A but not orexin B regulates lipid metabolism and leptin secretion in isolated porcine adipocytes. Domest Anim Endocrinol. 2018;63:59-68. PMID 29413903
10. 10

    Baranowska B, Wolińska-Witort E, Martyńska L, Chmielowska M, Baranowska-Bik A. Plasma orexin A, orexin B, leptin, neuropeptide Y (NPY) and insulin in obese women. Neuro Endocrinol Lett. 2005;26(4):293-6. PMID 16135994
11. 11

    Guerreiro S, Florence C, Rousseau E, Hamadat S, Hirsch EC, Michel PP. The sleep-modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine. Mol Pharmacol. 2015;87(3):525-32. PMID 25552485
12. 12

    Bian K, Liu C, Wang Y, Xue Y, Chen L. Orexin-B exerts excitatory effects on nigral dopaminergic neurons and alleviates motor disorders in MPTP parkinsonian mice. Neurosci Lett. 2021;765:136291. PMID 34666119
13. 13

    Ma X, Cao F, Cui J, Li X, Yin Z, Wu Y, Wang Q. Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation. Mol Biol Rep. 2024;51(1):669. PMID 38787465
14. 14

    Nicole P, Couvineau P, Jamin N, Voisin T, Couvineau A. Crucial role of the orexin-B C-terminus in the induction of OX1 receptor-mediated apoptosis: analysis by alanine scanning, molecular modelling and site-directed mutagenesis. Br J Pharmacol. 2015;172(21):5211-23. PMID 26282891
15. 15

    Haj-Dahmane S, Shen RY. The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. J Neurosci. 2005;25(4):896-905. PMID 15673670
16. 16

    Umezawa N, Arisaka H, Sakuraba S, Sugita T, Matsumoto A, Kaku Y, Yoshida K, Kuwana S. Orexin-B antagonized respiratory depression induced by sevoflurane, propofol, and remifentanil in isolated brainstem-spinal cords of neonatal rats. Respir Physiol Neurobiol. 2015;205:61-5. PMID 25448395
17. 17

    Rotondo M, Honisch C, Tartaggia S, Ruzza P. Circular dichroism study of orexin B under oxidative stress conditions. Molecules. 2023;28(2):484. PMID 36677542
18. 18

    Dauvilliers Y, Mignot E, Del Río Villegas R, Du Y, Hanson E, Inoue Y, Kadali H, Koundourakis E, Meyer S, Rogers R, Scammell TE, Sheikh SI, Swick T, Szakács Z, von Rosenstiel P, Wu J, Zeitz H, Murthy NV, Plazzi G, von Hehn C. Oral orexin receptor 2 agonist in narcolepsy type 1. N Engl J Med. 2023;389(4):309-321. PMID 37494485
19. 19

    Sun Y, Gao J. Oveporexton: the first-in-class orexin receptor 2 (OX2R) agonist approved for treatment of narcolepsy type 1 (NT1). Drug Discov Ther. 2026 Aug 19. PMID 42618292
20. 20

    van Lemmen M, Dahan A, Hang Y, Jansen SC, Lu H, Naylor M, Olsson T, Sheikh S, Sullivan D, Tolkoff M, van der Schrier R, van Velzen M, von Rosenstiel P, Wu RL, Meyer S. TAK-925 (danavorexton), an orexin receptor 2 agonist, reduces opioid-induced respiratory depression and sedation without affecting analgesia in healthy men. Anesthesiology. 2025;142(4):628-638. PMID 39804333