Arketamine Explained

Arketamine (developmental code names PCN-101, HR-071603), also known as (R)-ketamine or (R)-(-)-ketamine, is the (R)-(-) enantiomer of ketamine.[1] [2] [3] Similarly to racemic ketamine and esketamine, the S(+) enantiomer of ketamine, arketamine is biologically active; however, it is less potent as an NMDA receptor antagonist and anesthetic and thus has never been approved or marketed for clinical use as an enantiopure drug. Arketamine is currently in clinical development as a novel antidepressant.

Relative to esketamine, arketamine possesses 4 to 5 times lower affinity for the PCP site of the NMDA receptor.[4] In accordance, arketamine is significantly less potent than racemic ketamine and especially esketamine in terms of anesthetic, analgesic, and sedative-hypnotic effects. Racemic ketamine has weak affinity for the sigma receptor, where it acts as an agonist, whereas esketamine binds negligibly to this receptor, and so the sigma receptor activity of racemic ketamine lies in arketamine.[5] It was suggested that this action of arketamine may play a role in the hallucinogenic effects of racemic ketamine and that it may be responsible for the lowering of the seizure threshold seen with racemic ketamine. However several subsequent studies have indicated that esketamine is more likely to induce dissociative events,[6] [7] while studies in patients undergoing electroconvulsive therapy suggested that esketamine is a potent inducer of seizures.[8] Esketamine inhibits the dopamine transporter about 8-fold more potently than does arketamine, and so is about 8 times more potent as a dopamine reuptake inhibitor.[9] Arketamine and esketamine possess similar potency for interaction with the muscarinic acetylcholine receptors.[10]

Novel antidepressant

Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine in preclinical research.

In rodent studies, esketamine produced hyperlocomotion, prepulse inhibition deficits, and rewarding effects, while arketamine did not, in accordance with its lower potency as an NMDA receptor antagonist and dopamine reuptake inhibitor.[11] As such, arketamine may have a lower propensity for producing psychotomimetic effects and a lower abuse potential in addition to superior antidepressant efficacy.

A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the AMPA receptor, by a metabolite, (2R,6R)-hydroxynorketamine; as of 2017 it was unknown if this was happening in humans.[12] [13] Arketamine is an AMPA receptor agonist.[14]

Paradoxically, arketamine shows greater and longer-lasting rapid antidepressant effects in animal models of depression relative to esketamine.[15] [16] It has been suggested that this may be due to the possibility of different activities of arketamine and esketamine and their respective metabolites at the α7-nicotinic receptor, as norketamine and hydroxynorketamine are potent antagonists of this receptor and markers of potential rapid antidepressant effects (specifically, increased mammalian target of rapamycin function) correlate closely with their affinity for it.[17] [18] [19] The picture is unclear however, and other mechanisms have also been implicated.

Clinical development

As of November 2019, arketamine is under development for the treatment of depression under the developmental code names PCN-101 by Perception Neuroscience in the United States and HR-071603 by Jiangsu Hengrui Medicine in China.[20] [21]

See also

Notes and References

  1. Book: Ganellin CR, Triggle DJ . Dictionary of Pharmacological Agents. 21 November 1996. CRC Press. 978-0-412-46630-4. 1188–.
  2. Book: Yew DT . Ketamine: Use and Abuse. 6 March 2015. Taylor & Francis. 978-1-4665-8340-5. 269–.
  3. Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, Tadic A, Sienaert P, Wiegand F, Manji H, Drevets WC, Van Nueten L . 6 . Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study . Biological Psychiatry . 80 . 6 . 424–431 . September 2016 . 26707087 . 10.1016/j.biopsych.2015.10.018 . free .
  4. Book: Barash P, Cullen BF, Stoelting RK, Cahalan M, Stock MC, Ortega R . Clinical Anesthesia. 28 March 2012. Lippincott Williams & Wilkins. 978-1-4511-4795-7. 456–.
  5. Book: Verster JC, Brady K, Galanter M, Conrod P . Drug Abuse and Addiction in Medical Illness: Causes, Consequences and Treatment. 6 July 2012. Springer Science & Business Media. 978-1-4614-3375-0. 205–.
  6. Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J . Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET) . European Neuropsychopharmacology . 7 . 1 . 25–38 . February 1997 . 9088882 . 10.1016/S0924-977X(96)00042-9 . 26861697 .
  7. Engelhardt W . [Recovery and psychomimetic reactions following S-(+)-ketamine] . Der Anaesthesist . 46 . S38–S42 . March 1997 . Suppl 1 . 9163277 . 10.1007/pl00002463 . 24966884 .
  8. Zavorotnyy M, Kluge I, Ahrens K, Wohltmann T, Köhnlein B, Dietsche P, Dannlowski U, Kircher T, Konrad C . 6 . S -ketamine compared to etomidate during electroconvulsive therapy in major depression . European Archives of Psychiatry and Clinical Neuroscience . 267 . 8 . 803–813 . December 2017 . 28424861 . 10.1007/s00406-017-0800-3 . 22725552 .
  9. Nishimura M, Sato K . Ketamine stereoselectively inhibits rat dopamine transporter . Neuroscience Letters . 274 . 2 . 131–134 . October 1999 . 10553955 . 10.1016/s0304-3940(99)00688-6 . 10307361 .
  10. Book: Vuyk J, Schraag S . Advances in Modelling and Clinical Application of Intravenous Anaesthesia. 6 December 2012. Springer Science & Business Media. 978-1-4419-9192-8. 270–.
  11. Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K . 6 . R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects . Translational Psychiatry . 5 . 9 . e632 . September 2015 . 26327690 . 5068814 . 10.1038/tp.2015.136 .
  12. Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ . Classics in Chemical Neuroscience: Ketamine . ACS Chemical Neuroscience . 8 . 6 . 1122–1134 . June 2017 . 28418641 . 10.1021/acschemneuro.7b00074 .
  13. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA, Gould TD . 6 . NMDAR inhibition-independent antidepressant actions of ketamine metabolites . Nature . 533 . 7604 . 481–486 . May 2016 . 27144355 . 4922311 . 10.1038/nature17998 . 2016Natur.533..481Z .
  14. Yang C, Zhou W, Li X, Yang J . A bright future of researching AMPA receptor agonists for depression treatment . Expert Opinion on Investigational Drugs . 21 . 5 . 583–585 . May 2012 . 22375566 . 10.1517/13543784.2012.667399 . 19842307 . free .
  15. Zhang JC, Li SX, Hashimoto K . R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine . Pharmacology, Biochemistry, and Behavior . 116 . 137–141 . January 2014 . 24316345 . 10.1016/j.pbb.2013.11.033 . 140205448 .
  16. Hashimoto K . The R-Stereoisomer of Ketamine as an Alternative for Ketamine for Treatment-resistant Major Depression . Clinical Psychopharmacology and Neuroscience . 12 . 1 . 72–73 . April 2014 . 24851126 . 4022771 . 10.9758/cpn.2014.12.1.72 .
  17. van Velzen M, Dahan A . Ketamine metabolomics in the treatment of major depression . Anesthesiology . 121 . 1 . 4–5 . July 2014 . 24936919 . 10.1097/ALN.0000000000000286 . free .
  18. Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M, Green CE, O'Loughlin K, Torjman MC, Bernier M, Wainer IW . 6 . (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function . Anesthesiology . 121 . 1 . 149–159 . July 2014 . 24936922 . 4061505 . 10.1097/ALN.0000000000000285 .
  19. Singh NS, Zarate CA, Moaddel R, Bernier M, Wainer IW . What is hydroxynorketamine and what can it bring to neurotherapeutics? . Expert Review of Neurotherapeutics . 14 . 11 . 1239–1242 . November 2014 . 25331415 . 5990010 . 10.1586/14737175.2014.971760 .
  20. Hashimoto K . Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective . Psychiatry and Clinical Neurosciences . 73 . 10 . 613–627 . October 2019 . 31215725 . 6851782 . 10.1111/pcn.12902 .
  21. Web site: Arketamine - Jiangsu Hengrui Medicine . AdisInsight . Springer Nature Switzerland AG .

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