Relative to esketamine, arketamine possesses 4 to 5 times loweraffinity for thePCP site of theNMDA receptor.[2][6] In accordance, arketamine is significantly less potent than racemic ketamine and especially esketamine in terms ofanesthetic,analgesic, andsedative-hypnotic effects.[6] Racemic ketamine has weak affinity for thesigma 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] It was suggested that this action of arketamine may play a role in thehallucinogenic effects of racemic ketamine and that it may be responsible for the lowering of theseizure threshold seen with racemic ketamine.[7] However several subsequent studies have indicated that esketamine is more likely to induce dissociative events,[8][9] while studies in patients undergoing electroconvulsive therapy suggested that esketamine is a potent inducer of seizures.[10] Esketamineinhibits thedopamine transporter about 8-fold more potently than does arketamine, and so is about 8 times more potent as adopamine reuptake inhibitor.[11] Arketamine and esketamine possess similar potency for interaction with themuscarinic acetylcholine receptors.[12]
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] Arketamine is anAMPA receptor agonist.[17]
^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.PMID9088882.S2CID26861697.
^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.PMID28424861.S2CID22725552.
^abZhang 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.PMID24316345.S2CID140205448.
