data + articles · 1 listed
newest 2014spec sheet11 rows
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.
- demonstrated OX2-selective block is sufficient to promote sleep
- orally bioavailable, potent 2-SORA tool across multiple species
- underpins the rationale for selective OX2 drugs like seltorexant
- on-target sedation
Overview
one of the compounds that answered the 'do you even need OX1?' question. MK-1064 blocks only OX2 and still reliably promotes sleep in mice, rats, dogs and monkeys, which is the scientific basis for the whole 2-SORA idea (and later seltorexant). mostly a research/early-clinical molecule.
- MK-1064 helped prove that you can promote sleep by blocking only OX2, without touching OX1, the basis of the whole 2-SORA class.
- it was tested in four species' sleep models (mouse, rat, dog, rhesus monkey) during discovery.
- the 2-SORA idea it supports later became clinically important through seltorexant, a selective OX2 blocker studied in insomnia and depression.
Mechanism
MK-1064 is a selective -2 receptor (2-SORA); it potently and selectively blocks OX2R while largely sparing OX1R. the point of a 2-SORA is mechanistic economy: OX2R is the dominant receptor for the sleep/wake effects of orexin, so blocking it alone promotes sleep, while leaving OX1 (reward, appetite, anxiety) untouched, in theory a cleaner sleep drug. in merck's discovery work MK-1064 was optimized as a potent, orally bioavailable 2,5-disubstituted nicotinamide and showed sleep-promoting activity in mouse, rat, dog and rhesus models, establishing that OX2-selective block is sufficient for hypnotic effect (roecker 2013). it helped set up the clinical case that a 2-SORA could match dual antagonists for sleep with potentially fewer off-target effects.
receptor fingerprint
OX2R (-2 / HCRTR2)selective competitive antagonist
OX1R (-1 / HCRTR1)largely spared (selectivity for OX2)
Safetyrisks and cautions, not medical advice
investigational; no approved-label profile. as a 2-SORA the expected on-target effect is sleepiness; sparing OX1 may reduce some reward/appetite-related effects but the theoretical orexin-class risks (sleep paralysis, hallucinations, cataplexy-like weakness) hinge mostly on OX2, so they remain relevant. medicinal-chemistry hurdles noted during development included reversible cyp inhibition and p-glycoprotein efflux (roecker 2013). not available as a medicine.
History
developed by merck as a selective OX2 antagonist to characterize OX2-only pharmacology that dual antagonists (like suvorexant) could not isolate; the discovery paper appeared in 2013 (roecker 2013, chemmedchem). MK-1064 is a companion 2-SORA to MK-3697 and part of the lineage that made the OX2-selective approach credible, later carried into the clinic most prominently by seltorexant (janssen).
Reputation
a respected 2-SORA tool compound; among researchers it is a standard reference for OX2-selective effects, and it is part of the intellectual foundation for selective OX2 drugs. it is not a therapy and has limited public human data.
Subjective profileweighing the evidence above
A research tool that did its job, proving OX2 blockade alone is enough to bring sleep and clearing the path for drugs like seltorexant. It was never developed into a medicine and is not available as one, so its value now is the mechanism it established.
Resources
This entry is here for reference.
Research
1 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
what is a 2-SORA?
a selective orexin-2 receptor antagonist. it blocks only OX2, the main sleep/wake receptor, leaving OX1 alone. MK-1064 is a classic tool 2-SORA that showed this is enough to promote sleep.
can i take MK-1064 for sleep?
no; it is an investigational/research compound, not an approved medicine. the clinically relevant selective OX2 blocker is seltorexant, and the approved orexin sleep drugs are dual antagonists (daridorexant, lemborexant, suvorexant).
why block only OX2 instead of both receptors?
OX2 does most of the sleep/wake work, so blocking it alone promotes sleep, while sparing OX1 (reward, appetite, anxiety) might avoid some off-target effects. MK-1064 was one of the compounds that validated that idea in animals.
is a 2-SORA better than a DORA for sleep?
not clearly. 2-SORAs match DORAs for the core sleep effect in principle, and might be cleaner on OX1-linked effects, but the approved drugs are all DORAs; the selective-OX2 approach is still being proven clinically (seltorexant).
Adverse effects
- on-target sedation
Notes and cautions
- orexin-class theoretical cautions (OX2-linked) still apply
- development hurdles: reversible CYP inhibition, P-gp efflux