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Esketamine

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Esketamine
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180px
Systematic (IUPAC) name
(S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
Trade names Ketanest S
AHFS/Drugs.com Consumer Drug Information
Identifiers
33643-46-8 7pxN
N01AX14
PubChem CID 182137
DrugBank DB01221 7pxY
ChemSpider 158414 7pxN
UNII 50LFG02TXD 7pxY
ChEBI CHEBI:6121 7pxY
ChEMBL CHEMBL742 7pxY
Chemical data
Formula C13H16ClNO
237.725 g/mol
 14pxN (what is this?)  (verify)
Main article: Ketamine

Esketamine (also (S)-ketamine or S(+)-ketamine) (brand name Ketanest S) is a general anaesthetic and a dissociative. It is the S(+) enantiomer of the drug ketamine, a general anaesthetic. Esketamine acts primarily as a non-competitive NMDA receptor antagonist, but is also a dopamine reuptake inhibitor. As of July 2014, it is in phase II clinical trials for treatment-resistant depression (TRD).[1]

Pharmacology

Esketamine is approximately twice as potent as racemic ketamine.[2] It is eliminated from the human body more quickly than R(−)-ketamine or racemic ketamine, although R(−)-ketamine slows its elimination.[3]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than R(−)-ketamine or racemic ketamine. Esketamine inhibits dopamine transporters eight times more than R(−)-ketamine.[4] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.[5][6] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.[2][7]

Esketamine has an affinity for the PCP binding site of the NMDA receptor 3-4 times higher than that of R(−)-ketamine. Unlike R(−)-ketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while R(−)-ketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while R(−)-ketamine is reportedly more relaxing.[7] However, other studies have found no difference between the isomers in the patient's level of vigilance.[5]

Potential use as an antidepressant

Johnson & Johnson is developing a nasal spray formulation of esketamine as a treatment for depression in patients that have been unresponsive to other antidepressants in the United States.[1] As of July 2014, phase II clinical trials of intranasal esketamine sponsored by the Johnson & Johnson subsidiary Janssen Pharmaceutica are underway.[1][8] Other pharmaceutical companies are also developing new antidepressant drugs that act similarly to ketamine, including Naurex's rapastinel (GLYX-13) and NRX-1074, Cerecor's CERC-301, and VistaGen's AV-101.

Although most studies suggest that esketamine is preferable for medical uses, a 2013 study found that the antidepressant effect of R(−)-ketamine lasted longer than those of S(+)-ketamine in mice.[9]

See also

References

  1. ^ a b c Wijesinghe, R (2014). "Emerging Therapies for Treatment Resistant Depression". Ment Health Clin 4 (5): 56. ISSN 2168-9709. 
  2. ^ a b PMID 9893910 (PubMed)
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  3. ^ PMID 11719729 (PubMed)
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  4. ^ PMID 10553955 (PubMed)
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  5. ^ a b PMID 1443509 (PubMed)
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  6. ^ PMID 7840417 (PubMed)
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  7. ^ a b PMID 9088882 (PubMed)
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  8. ^ http://clinicaltrials.gov/show/NCT01998958
  9. ^ Zhang, J. C.; Li, S. X.; Hashimoto, K. (2014). "R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine". Pharmacology Biochemistry and Behavior 116: 137–141. PMID 24316345. doi:10.1016/j.pbb.2013.11.033.  edit