Chemistry:Ketamir-2

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Ketamir-2, or simply Ketamir, also known as oral ketamine analogue or as 1-(2-chlorophenyl)-N-methyl-2-oxocyclopentan-1-amine, is an NMDA receptor antagonist closely related ketamine and other arylcyclohexylamines which is under development for the treatment of depressive disorders and other conditions such as neuropathic pain.[1][2][3][4] It is the analogue of ketamine in which the 6-membered cyclohexane ring has been replaced with a 5-membered cyclopentane ring.[3] Ketamir-2 is orally active.[3]

Pharmacology

Ketamir-2 is a very low-affinity antagonist of the phencyclidine (PCP) site of the NMDA receptor.[3] Its affinity (IC50) for the PCP site of the NMDA receptor is approximately 100 μM, whereas that of ketamine (Ki) has been found to be about 660 nM (which is ~150-fold higher affinity).[3][5] Ketamir-2 also has a major active metabolite, desmethylketamir (norketamir), which has an affinity (IC50) for the PCP site of the NMDA receptor of about 470 μM.[3] Ketamir-2 showed no activity at other sites besides the PCP site of the NMDA receptor when screened against a panel of 40 receptors, transporters, enzymes, and ion channels.[3] This is in contrast to ketamine, which shows appreciable affinities for a variety of other targets.[3] As such, Ketamir-2 is claimed to be more selective than ketamine.[3]

Whereas ketamine is a substrate for P-glycoprotein and this might impede its absorption and distribution, Ketamir-2 does not bind to this protein.[3][4] Relatedly, Ketamir-2 shows improved oral bioavailability relative to ketamine and might have better blood–brain barrier permeability.[3][4] Ketamir-2 displays a pharmacokinetic profile in animals of rapid absorption and short elimination half-life.[3] Whereas ketamine produces hyperlocomotion in rodents, a stimulant- and putatively psychotic-like effect, Ketamir-2, depending on the dose, either did not affect locomotor activity or decreased it.[3] Ketamir-2 showed antidepressant-like, anxiolytic-like, and analgesic-like effects in animal models.[3]

History

Ketamir-2 is under development by MIRA Pharmaceuticals.[1][2] As of July 2024, it is in the preclinical research stage of development.[1][2] In June 2025, the first journal article about Ketamir-2 was published.[3] According to the Drug Enforcement Administration (DEA), Ketamir-2 is not a controlled substance in the United States as of 2024.[4]

See also

References

  1. ↑ 1.0 1.1 1.2 "MIRA Pharmaceuticals". 1 July 2024. https://adisinsight.springer.com/drugs/800076274. 
  2. ↑ 2.0 2.1 2.2 "Delving into the Latest Updates on Ketamir-2 with Synapse". 31 May 2025. https://synapse.patsnap.com/drug/9e99e8eb97b24396939d229176a24e1e. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 "KETAMIR-2, a new molecular entity and novel ketamine analog". Frontiers in Pharmacology 16. 20 June 2025. doi:10.3389/fphar.2025.1606976. ISSN 1663-9812. 
  4. ↑ 4.0 4.1 4.2 4.3 "DEA Says This New Oral Ketamine Analog Is Not a Controlled Substance". 9 August 2024. https://doubleblindmag.com/ketamir-2/. 
  5. ↑ "The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor". PLOS ONE 8 (3). 2013. doi:10.1371/journal.pone.0059334. PMID 23527166. Bibcode: 2013PLoSO...859334R. 




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