Pharmacological characterization of SAGE‐718, a novel positive allosteric modulator of N‐methyl‐d‐aspartate receptors

• Published in: British journal of pharmacology 2024-04, Vol.181 (7), p.1028-1050
• Main Authors: Beckley, Jacob T., Aman, Teresa K., Ackley, Michael A., Kazdoba, Tatiana M., Lewis, Michael C., Smith, Anne C., Farley, Brandon J., Dai, Jing, Deats, Wayne, Hoffmann, Ethan, Robichaud, Albert J., Doherty, James J., Quirk, Michael C.
• Format: Article
• Language: English
• Subjects: Allosteric properties; Cholesterol; Cognitive ability; cognitive dysfunction; EEG; Electrophysiological recording; Epilepsy; Excitatory postsynaptic potentials; Glutamic acid receptors (ionotropic); Ketamine; Kinetics; N-Methyl-D-aspartic acid receptors; Neostriatum; neuroactive steroids; Neurodegeneration; neuropharmacology, pharmacodynamics, allosteric modulation; Neurosteroids; Neurotransmission; N‐methyl‐d‐aspartate receptor; Phencyclidine; Seizures; Spiny neurons; Steroid hormones; Steroids; translational pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16235

Background and Purpose Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)‐hydroxycholesterol (24(S)‐HC), which is an N‐methyl‐d‐aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. Experimental Approach Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE‐718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. Key Results SAGE‐718 potentiated GluN1/GluN2A‐D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE‐718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine‐evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE‐718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)‐HC depletion caused by 7‐dehydrocholesterol reductase inhibition. Finally, SAGE‐718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. Conclusions and Implications These findings provide strong evidence that SAGE‐718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.