Chemical compound
Pharmaceutical compound
Arketamine (developmental code namesPCN-101 ,HR-071603 ), also known as(R )-ketamine or(R )-(−)-ketamine , is the (R )-(−)enantiomer ofketamine .[ 1] [ 2] [ 3] racemic ketamine andesketamine , theS (+) enantiomer of ketamine, arketamine isbiologically active ; however, it is less potent as anNMDA receptor antagonist andanesthetic and thus has never been approved or marketed forclinical use as anenantiopure drug .[ 1] [ 3] antidepressant .[ 4] [ 5]
Relative to esketamine, arketamine possesses 4 to 5 times loweraffinity for thePCP site of theNMDA receptor .[ 2] [ 6] anesthetic ,analgesic , andsedative-hypnotic effects.[ 6] sigma receptor , where it acts as anagonist , whereas esketamine binds negligibly to this receptor, and so the sigma receptor activity of racemic ketamine lies in arketamine.[ 7] hallucinogenic effects of racemic ketamine and that it may be responsible for the lowering of theseizure threshold seen with racemic ketamine.[ 7] [ 8] [ 9] [ 10] inhibits thedopamine transporter about 8-fold more potently than does arketamine, and so is about 8 times more potent as adopamine reuptake inhibitor .[ 11] muscarinic acetylcholine receptors .[ 12]
Novel antidepressant [ edit ] Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine inpreclinical research .[ 13]
Inrodent studies , esketamine producedhyperlocomotion ,prepulse inhibition deficits, andrewarding effects , while arketamine did not, in accordance with its lower potency as an NMDA receptor antagonist and dopamine reuptake inhibitor.[ 14] psychotomimetic effects and a lowerabuse potential in addition to superior antidepressant efficacy.[ 14]
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, theAMPA receptor , by a metabolite, (2R,6R)-hydroxynorketamine ; as of 2017 it was unknown if this was happening in humans.[ 15] [ 16] AMPA receptor agonist .[ 17]
Paradoxically, arketamine shows greater and longer-lasting rapidantidepressant effects inanimal models ofdepression relative to esketamine.[ 13] [ 18] [ 14] metabolites at theα7 -nicotinic receptor , asnorketamine andhydroxynorketamine are potentantagonists of this receptor and markers of potential rapid antidepressant effects (specifically, increasedmammalian target of rapamycin function) correlate closely with their affinity for it.[ 19] [ 20] [ 21] [ 14]
Clinical development [ edit ] As of November 2019, arketamine is under development for the treatment ofdepression under the developmental code names PCN-101 by Perception Neuroscience in theUnited States and HR-071603 byJiangsu Hengrui Medicine inChina .[ 22] [ 4] [ 5] antidepressant effectiveness in acontrolled phase 2a clinical trial .[ 23] [ 24]
^a b Ganellin CR, Triggle DJ (21 November 1996).Dictionary of Pharmacological Agents ISBN 978-0-412-46630-4 ^a b Yew DT (6 March 2015).Ketamine: Use and Abuse ISBN 978-1-4665-8340-5 ^a b Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, et al. (September 2016)."Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study" .Biological Psychiatry .80 (6):424– 431.doi :10.1016/j.biopsych.2015.10.018 PMID 26707087 . ^a b Hashimoto K (October 2019)."Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective" .Psychiatry and Clinical Neurosciences .73 (10):613– 627.doi :10.1111/pcn.12902 .PMC 6851782 PMID 31215725 . ^a b "Arketamine - Jiangsu Hengrui Medicine" .AdisInsight . Springer Nature Switzerland AG.^a b Barash P, Cullen BF, Stoelting RK, Cahalan M, Stock MC, Ortega R (28 March 2012).Clinical Anesthesia ISBN 978-1-4511-4795-7 ^a b Verster JC, Brady K, Galanter M, Conrod P, eds. (6 July 2012).Drug Abuse and Addiction in Medical Illness: Causes, Consequences and Treatment ISBN 978-1-4614-3375-0 ^ Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). "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.doi :10.1016/S0924-977X(96)00042-9 .PMID 9088882 .S2CID 26861697 . ^ Engelhardt W (March 1997). "[Recovery and psychomimetic reactions following S-(+)-ketamine]".Der Anaesthesist .46 (Suppl 1):S38 – S42 .doi :10.1007/pl00002463 .PMID 9163277 .S2CID 24966884 . ^ Zavorotnyy M, Kluge I, Ahrens K, Wohltmann T, Köhnlein B, Dietsche P, et al. (December 2017). "S -ketamine compared to etomidate during electroconvulsive therapy in major depression".European Archives of Psychiatry and Clinical Neuroscience .267 (8):803– 813.doi :10.1007/s00406-017-0800-3 .PMID 28424861 .S2CID 22725552 . ^ Nishimura M, Sato K (October 1999). "Ketamine stereoselectively inhibits rat dopamine transporter".Neuroscience Letters .274 (2):131– 134.doi :10.1016/s0304-3940(99)00688-6 .PMID 10553955 .S2CID 10307361 . ^ Vuyk J, Schraag S (6 December 2012).Advances in Modelling and Clinical Application of Intravenous Anaesthesia ISBN 978-1-4419-9192-8 ^a b Zhang JC, Li SX, Hashimoto K (January 2014). "R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine".Pharmacology, Biochemistry, and Behavior .116 :137– 141.doi :10.1016/j.pbb.2013.11.033 .PMID 24316345 .S2CID 140205448 . ^a b c d Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, et al. (September 2015)."R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects" .Translational Psychiatry .5 (9): e632.doi :10.1038/tp.2015.136 .PMC 5068814 PMID 26327690 . ^ Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ (June 2017). "Classics in Chemical Neuroscience: Ketamine".ACS Chemical Neuroscience .8 (6):1122– 1134.doi :10.1021/acschemneuro.7b00074 .PMID 28418641 . ^ Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. (May 2016)."NMDAR inhibition-independent antidepressant actions of ketamine metabolites" .Nature .533 (7604):481– 486.Bibcode :2016Natur.533..481Z .doi :10.1038/nature17998 .PMC 4922311 PMID 27144355 . ^ Yang C, Zhou W, Li X, Yang J (May 2012)."A bright future of researching AMPA receptor agonists for depression treatment" .Expert Opinion on Investigational Drugs .21 (5):583– 585.doi :10.1517/13543784.2012.667399 PMID 22375566 .S2CID 19842307 . ^ Hashimoto K (April 2014)."The R-Stereoisomer of Ketamine as an Alternative for Ketamine for Treatment-resistant Major Depression" .Clinical Psychopharmacology and Neuroscience .12 (1):72– 73.doi :10.9758/cpn.2014.12.1.72 .PMC 4022771 PMID 24851126 . ^ van Velzen M, Dahan A (July 2014)."Ketamine metabolomics in the treatment of major depression" .Anesthesiology .121 (1):4– 5.doi :10.1097/ALN.0000000000000286 PMID 24936919 . ^ Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M, Green CE, et al. (July 2014)."(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function" .Anesthesiology .121 (1):149– 159.doi :10.1097/ALN.0000000000000285 .PMC 4061505 PMID 24936922 . ^ Singh NS, Zarate CA, Moaddel R, Bernier M, Wainer IW (November 2014)."What is hydroxynorketamine and what can it bring to neurotherapeutics?" .Expert Review of Neurotherapeutics .14 (11):1239– 1242.doi :10.1586/14737175.2014.971760 .PMC 5990010 PMID 25331415 . ^ "Arketamine - ATAI Life Sciences" .AdisInsight . 10 June 2024. Retrieved23 October 2024 .^ Kim JW, Suzuki K, Kavalali ET, Monteggia LM (January 2024)."Ketamine: Mechanisms and Relevance to Treatment of Depression" .Annu Rev Med .75 :129– 143.doi :10.1146/annurev-med-051322-120608 PMID 37729028 . ^ "atai Life Sciences Announces Results from Phase 2a Trial of PCN-101 (R-ketamine) for Treatment-Resistant Depression" .atai Life Sciences . 9 January 2023. Retrieved23 October 2024 .
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