Orexin: nootropics and compounds | sci-wiki

Seltorexant

Seltorexant is a selective orexin-2 receptor antagonist in advanced clinical development for insomnia and major depressive disorder. By blocking the orexin-2 receptor that keeps the brain awake, it shortens the time to fall asleep and improves sleep maintenance, with a short half-life engineered to limit next-day grogginess. In randomized trials it has matched or outperformed zolpidem on key sleep measures with fewer treatment-emergent side effects, and it shows particular promise for depression accompanied by insomnia.

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Peptide

GB-115

GB-115 is a cleverly designed dipeptide anxiolytic that eases anxiety while keeping the mind clear, a combination almost nothing else in its category manages. Rather than sedating, it blocks the cholecystokinin CCK-1 receptor, a pathway tied specifically to chronic anxiety and panic, and in a clinical study of generalized anxiety disorder it actually sharpened attention and reaction time while it worked. For those seeking calm without the fog, weakness, or dependence of classic sedatives, GB-115 is a genuinely intriguing research anxiolytic.

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Nootropic

Orexin-A

Orexin-A, also known as hypocretin-1, is a 33-amino-acid neuropeptide produced by a small population of neurons in the lateral hypothalamus that is central to promoting wakefulness and arousal. It is one of two orexin peptides cut from a single precursor and signals through two G-protein-coupled receptors. Narcolepsy type 1 is essentially an orexin-deficiency disease, in which the roughly 70,000 orexin-producing neurons are selectively destroyed and cerebrospinal-fluid orexin becomes undetectable; this is the rationale for orexin-2 receptor agonists now in clinical trials as the first mechanism-based, replacement-style treatment rather than a symptomatic stimulant. Since its discovery in 1998 the orexin system has become a major target in sleep medicine.

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Nootropic

Orexin-A Fragment 17-33

Orexin-A fragment 17-33 is a shortened, C-terminal portion of the neuropeptide orexin-A, comprising the last seventeen of its thirty-three amino acids. It belongs to a group of truncated orexin peptides studied to map which parts of the parent molecule are needed to activate orexin receptors. Research on such fragments showed that the activity of orexin-A resides mainly in its C-terminal end, and the fragment is used chiefly as a laboratory tool for probing the orexin system rather than as a medicine.

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Nootropic

Orexin-B

Orexin-B, also known as hypocretin-2, is a 28-amino-acid neuropeptide made in the hypothalamus that, together with orexin-A, promotes wakefulness, arousal, and appetite. It is cut from the same precursor as orexin-A but lacks internal disulfide bonds and preferentially activates the orexin type 2 receptor. That receptor is the target of the dual orexin receptor antagonists suvorexant, lemborexant, and daridorexant, which treat insomnia by blocking the same signaling whose loss causes narcolepsy, making the two conditions pharmacological mirror images; one of these drugs was also reported to acutely lower tau and amyloid-beta in human cerebrospinal fluid. The orexin system was discovered in 1998.

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Sleep Support

Lemborexant

Lemborexant, sold under the brand name Dayvigo, is a prescription sleep medication of a newer class called dual orexin receptor antagonists. Developed by Eisai and approved in the United States in 2019, it is used to treat insomnia in adults, helping with both falling asleep and staying asleep. Rather than broadly sedating the brain like older sleeping pills, it works by blocking orexin, a signal that promotes wakefulness, and it is classed as a controlled substance.

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Sleep Support

Almorexant

actelion's dual orexin receptor antagonist and the first DORA to reach late clinical trials for insomnia; development was halted in 2011 over tolerability/safety concerns, but it proved the concept and is still used as a research tool.

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Sleep Support

Daridorexant

idorsia's dual orexin receptor antagonist (quviviq); the newest fda-approved DORA for insomnia, designed for a short half-life so it quiets nighttime wake-drive without much next-day hangover.

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Nootropic

Declozindol

A dechlorinated mazindol analogue tuned to be a clean noradrenaline reuptake blocker plus a partial orexin-2 agonist; an orexin-forward wake drug aimed at narcolepsy.

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Sleep Support

Filorexant

merck's second dual orexin antagonist (MK-6096); a shorter-acting DORA studied for insomnia and then, unsuccessfully, for depression, before development was discontinued.

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Sleep Support

JNJ-54717793

janssen's brain-penetrant selective orexin-1 receptor antagonist (~50-fold OX1 over OX2); a research tool that blunts panic/anxiety responses in rats without sedating them, illustrating the anti-anxiety angle of OX1 blockade.

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Sleep Support

MK-1064

merck's selective orexin-2 receptor antagonist (2-SORA); a potent, orally active tool/candidate used to show that blocking OX2 alone is enough to promote sleep across species.

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Sleep Support

Nivasorexant

idorsia's ACT-539313; the first selective orexin-1 receptor antagonist (SO1RA) taken into human trials, aimed at conditions like binge eating and anxiety rather than sleep, since blocking OX1 alone does not strongly promote sleep.

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Sleep Support

SB-334867

the original selective orexin-1 receptor antagonist; a non-drug research tool used in thousands of preclinical studies of addiction, feeding, anxiety and reward; not a therapy, and with known chemical-stability quirks.

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Sleep Support

Suvorexant

merck's belsomra; the first fda-approved dual orexin receptor antagonist (2014), a proof-of-concept that blocking the wake signal treats insomnia; effective but its longer half-life makes next-day grogginess more of an issue.

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Eugeroic

TAK-861

Oveporexton (TAK-861), approved by the FDA on 5 August 2026 as Orzeyful; the first oral orexin receptor 2 selective agonist licensed for narcolepsy type 1, and the first approved treatment aimed at the cause of the disease rather than its symptoms.

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Eugeroic

TAK-925

danavorexton (TAK-925); the first-in-class, injectable OX2R-selective orexin agonist that proved wakefulness can be pharmacologically restored, now aimed at reversing anesthetic and opioid sedation.

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Eugeroic

TAK-994

TAK-994; the first oral OX2R orexin agonist to show major narcolepsy efficacy in phase 2, halted for dose-dependent liver toxicity, and the direct predecessor to oveporexton (TAK-861).

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Sleep Support

Vornorexant

taisho's investigational dual orexin receptor antagonist (TS-142) with an unusually short half-life, designed for fast sleep onset and minimal next-day residual effects; in clinical development in japan.

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