Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects

Authors

Jeffrey S. Burgdorf, Gate Neurosciences, Inc., Carmel, Indiana, USA.
Xiao-Lei Zhang, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA.Follow
Patric K. Stanton, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA.Follow
Joseph R. Moskal, Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, Illinois, USA.
John E. Donello, Gate Neurosciences, Inc., Carmel, Indiana, USA.

Author Type(s)

Faculty

DOI

10.1093/ijnp/pyac043

Journal Title

The International Journal of Neuropsychopharmacology

First Page

979

Last Page

991

Document Type

Article

Publication Date

12-12-2022

Department

Cell Biology and Anatomy

Abstract

BACKGROUND: The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity. METHODS: NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the chronic social deficit mouse model. Target engagement and the safety/tolerability profile was assessed using phencyclidine-induced hyperlocomotion and rotarod rodent models. RESULTS: Following a single oral dose, zelquistinel (0.1-100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/ cerebrospinal fluid concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting that zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited phencyclidine (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance. CONCLUSIONS: Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation of synaptic transmission.

Recommended Citation

Burgdorf, J. S., Zhang, X., Stanton, P. K., Moskal, J. R., & Donello, J. E. (2022). Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects. The International Journal of Neuropsychopharmacology, 25 (12), 979-991. https://doi.org/10.1093/ijnp/pyac043