GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists

Abstract

Introduction: The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects.

Areas covered: The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies.

Expert opinion: NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.

Figure 1. GLYX-13 is an NMDAR functional glycine site partial agonist

(A) The effects of GLYX-13 on NMDA currents in oocytes. Cells were injected with e1/z1 cRNA, voltage-clamped at −80 mV in the presence of 100 µM NMDA, varying concentrations of GLYX-13, and no exogenous glycine. Data are expressed as a percentage of the current elicited by 10 µM glycine in the same cell, usually in the same trial. Results from nine cells injected with e1/z1 cRNA; error bars indicate SEM. (B) The effects of GLYX-13 (0.1 – 100 µM) on LTP induced by a high-frequency stimulus train (3 × 100 Hz/500 ms) at Schaffer collateral–CA1 synapses. Each point represents Mean ± SEM of normalized field EPSP slope. (C) Pharmacologically isolated NMDAR currents were recorded from whole-cell patch clamp recordings of CA1 pyramidal neurons in slices. GLYX-13 by itself (left-most symbols) elicited increased NMDAR channel current to 20% the maximum current elicited by the full-agonist D-serine. GLYX-13 added in increasing concentrations shifted the dose response of D-serine to the right. Kp = 1.3 µM was calculated using the Stephenson method [39]. Data were adapted from [29] and [33] with permission of Elsevier.

Figure 2. GLYX-13 is a cognitive enhancer

(A– C) The effects of an optimal cognitive enhancing dose of GLYX-13 (1 mg/kg, IV, 15 min post-dosing) in young adult (3 months) or learning-impaired aged (27 months old) rats in hippocampal-dependent trace eyeblink conditioning (A), alternating T-maze (B), and Morris water maze (C) tests. (D) GLYX-13 (1 mg/kg, IV, 15 min post-dosing) in young adult (3 months) rats facilitated positive emotional learning as measured by rates of hedonic 50 kHz ultrasonic vocalizations in response to a conditioned stimulus that predicts heterospecific rough-and-tumble play. Data are expressed as Mean ± SEM. *p < 0.05 Fisher’s PLSD post hoc test vs. vehicle. Data adapted from [30,31,33] with permission of Elsevier.

Figure 3. GLYX-13 has antidepressant-like properties without psychotomimetic side effects in rats

(A – D) The antidepressant-like effects of an optimal antidepressant-like dose of GLYX-13 (3 mg/kg IV) in the rat Porsolt test measured at 1 h (A) or 24 h (B) post-dosing G, the novelty-induced hypophagia test 1 h post-dosing (C) or the learned helplessness test 24 h post dosing (D). GLYX-13 does not show ketamine-like discriminative stimulus effects (E) or sedative effects (F) in rats trained to discriminate 10 mg/kg ketamine from saline. (G – H) GLYX-13 (10 mg/kg IV) does not show ketamine-like rewarding effects in the conditioned place preference (G) or sensory-motor gating deficits in the pre-pulse inhibition (H) tests in rats. Data are expressed as Mean ± SEM. *p < 0.05 Fisher’s PLSD post hoc test vs. vehicle. Data adapted from [34] with permission of Nature Publishing Group.

Figure 4. The antidepressant effects of GLYX-13 are due to NMDAR-triggered synaptic plasticity

GLYX-13 (3 mg/kg IV, 24 h post-dosing): (A) enhances the magnitude of hippocampus ex vivo long-term potentiation, (B) antidepressant-like effect is blocked by the AMPA/kainate antagonist NBQX, (C) increases hippocampus NR2B current, and (D) increases cell surface expression of NR2B and GluR1 protein levels in the medial prefrontal cortex and hippocampus. Data are expressed as Mean ± SEM. *p < 0.05 Fisher’s PLSD post hoc test vs. vehicle. Data adapted from [34] with permission of Nature Publishing Group.

Figure 5. GLYX-13 reduces depression scores assessed as HDRS-17 score and does not cause psychotomimetic side effects assessed as BPRS+ scores

(A) HDRS-17 scores are presented as difference from baseline. Mean ± SEM. Baseline scores were 26.1 (n = 33) placebo, and 26.1 (n = 25), 25.2 (n = 20), 25.1 (n = 17), and 24.6 (n = 21) for GLYX-13, 1, 5, 10, and 30 mg/kg, respectively. *p < 0.05 for 10 mg/kg compared to placebo at that time point. *p < 0.05 ANCOVA for 5 and 10 mg/kg compared to placebo. GLYX-13 reduces depressive symptoms assessed as Bech-6 scores. (B) GLYX-13 does not cause psychotomimetic side effects assessed as BPRS+ scores. Mean + SEM, SEM were all 0.02 or less. Placebo, n = 33, GLYX-13 1 mg/kg, n = 25, 5 mg/kg, n = 20, 10 mg/kg, n = 17, 30 mg/kg, n = 21.