Relative to esketamine, arketamine possesses 4 to 5 times lower
affinity for the
PCP site of the
NMDA receptor.[2][6] In accordance, arketamine is significantly less potent than racemic ketamine and especially esketamine in terms of
anesthetic,
analgesic, and
sedative-hypnotic effects.[6] 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.[7] 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.[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] 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.[11] Arketamine and esketamine possess similar potency for interaction with the
muscarinic acetylcholine receptors.[12]
Novel antidepressant
Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine in
preclinical research.[13]
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.[15][16] Arketamine is an
AMPA receptor agonist.[17]
Paradoxically, arketamine shows greater and longer-lasting rapid
antidepressant effects in
animal models of
depression relative to esketamine.[13][18][14] 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.[19][20][21] The picture is unclear however, and other mechanisms have also been implicated.[14]
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.[4][5]
^
abBarash P, Cullen BF, Stoelting RK, Cahalan M, Stock MC, Ortega R (28 March 2012).
Clinical Anesthesia. Lippincott Williams & Wilkins. pp. 456–.
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^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.
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^Engelhardt W (March 1997). "[Recovery and psychomimetic reactions following S-(+)-ketamine]". Der Anaesthesist. 46 (Suppl 1): S38–S42.
doi:
10.1007/pl00002463.
PMID9163277.
S2CID24966884.
^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.
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