NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.

Background: Ampakines are a family of molecules that enhance the functioning of AMPA-glutamate receptors (AMPAR). High-impact ampakines completely offset receptor desensitization and enhance agonist binding affinity, while low-impact ampakines only modestly affect receptor desensitization and do not alter agonist binding affinity. Nonetheless, little is known about AMPAR recovery following ampakine treatment. Methods: Herein, we study the effects of ampakines on AMPAR recovery and the interaction between high- and low-impact ampakines. Results: The high-impact ampakine CX729 did not induce any current in the absence of glutamate, but it dramatically increased glutamate-induced steady-state inward currents. Recoveries from the enhancement were significantly slower than those for the low-impact ampakine CX516, as was also seen on miniature synaptic currents. Electrophysiological interaction studies suggest that high- and low-impact ampakines may have different binding sites. We further investigated the induction of the potentiated response by measuring glutamate-induced responses after transient applications of CX729 or CX729 plus glutamate. Under both circumstances, subsequent application of glutamate yielded comparably potentiated responses. Furthermore, the recovery time was not different if saline was substituted for glutamate during the recovery period. Conclusions: These observations show that AMPAR potentiation by CX729 does not require the simultaneous presence of glutamate, nor is the slow reversal of the effects of the ampakine altered by subsequent receptor activation. Hence, the slow recovery from the effects of these select ampakines on the AMPAR may be the result of slow dissociation kinetics. We posit that the slow recovery of AMPAR from high-impact ampakines may contribute to the seizurogenic effects of this drug class and that high-impact ampakines that allow for more rapid AMPAR recovery may be safer and more clinically viable candidates.

Background: The GABA_A receptor (GABAAR) potentiator, KRM-II-81, is being developed as a novel antiseizure medication with reduced potential for sedation, tolerance development, and abuse liability. Although KRM-II-81 has been shown to provide antiseizure protection against a broad array of seizure induction paradigms, seizures induced by viral vectors have not been previously studied. GABAARs with specific α subunit compositions have been studied in relation to the reduced side-effect liability of KRM-II-81; however, the role of β subunit composition has yet to be determined. Methods: In the present study, KRM-II-81 was studied against handling-induced seizures in Theiler’s murine encephalomyelitis virus (TMEV)-infected mice. Results: An intracerebral infusion of TMEV on day 0 increased the cumulative seizure burden in mice when assessed for handling-induced seizures on days 3–7. KRM-II-81 (15 mg/kg, p.o., bid) nearly completely suppressed seizures in TMEV-infected mice over the course of daily treatments. The number of the most severe seizures (stage 5, tonic/clonic seizures) in the mice was suppressed to zero by KRM-II-81. Although the selectivity of KRM-II-81 for GABAAR α2/3 receptor subtypes might imbue KRM-II-81 with a reduced side-effect liability, other mechanisms are possible, and the potentiation of β1-containing GABAARs has been implicated in inducing sedation. The role of β subunit composition has yet to be determined for KRM-II-81. In electrophysiological studies with cells transfected with α_xβ₁γ₂ or α_xβ₃γ₂, KRM-II-81 preferentially potentiated GABA responses in cells containing β3 subunits in α2/3-containing GABAARs. Conclusions: The present findings confirm the robust antiseizure activity of KRM-II-81, now extended to a virus-induction model, and suggest a possible role of reduced β1-potentiation in the low side-effect profile of KRM-II-81.