Arketamine

Arketamine, also (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. 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, also (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. 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. Relative to esketamine, arketamine possesses 4–5 times lower affinity for the PCP site of the NMDA receptor. 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. It has been 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. 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. Arketamine and esketamine possess similar potency for interaction with the muscarinic acetylcholine receptors. Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine. 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. 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. Arketamine is a AMPA receptor agonist. Paradoxically, arketamine shows greater and longer-lasting rapid antidepressant effects in animal models of depression relative to esketamine. 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. The picture is unclear however, and other mechanisms have also been implicated.