Rapastinel

Rapastinel (GLYX-13) is a potent NMDAR modulator capable of crossing the blood-brain barrier, and it exhibits extremely high affinity for human NMDAR (EC₅₀=0.0017-9.9 nM). Rapastinel enhances ERK signaling and activates the mTOR pathway, thereby upregulating the expression of BDNF and VGF, and inducing significant neuroplastic changes such as enhanced LTP and increased mature dendritic spine density in the hippocampus. Rapastinel moderately elevates the efflux of dopamine, norepinephrine and 5-HT in the prefrontal cortex, and uniquely avoids side effects of traditional antidepressants such as dissociation, addiction or sedation. Rapastinel is applicable to the research of major depressive disorder and hepatocellular carcinoma^{[1][2][3][4][5]}. In Vitro:Rapastinel (20 μM; 4 h) reverses the propofol-induced reductions in CaMKII phosphorylation, AKT phosphorylation, HIF-1α expression, intracellular Ca²⁺ concentration, glycolysis protein levels, adhesion molecule levels, and tumor cell-endothelial cell adhesion in Huh7 tumor conditioned medium-treated HUVECs^[2].
Rapastinel (tested concentrations; 15 min preincubation, 15 min with [³H] MK-801) partially enhances [³H] MK-801 binding to recombinant human NR2A-, NR2B-, NR2C-, and NR2D-containing NMDARs with EC₅₀ values of 9.8 pM, 9.9 nM, 2.2 pM, and 1.7 pM, respectively^[5].
Rapastinel (100 nM-1 μM) has its modulatory effects on NMDAR-mediated calcium mobilization completely abolished by mutations of critical amino acids in the NR2A^(R392E) or NR2B^(R393E) NMDAR amino terminal domain, confirming this domain is required for rapastinel's activity^[5]. In Vivo:Rapastinel (5-10 mg/kg; intravenous injection, once daily for 3 consecutive days) exerts rapid antidepressant-like effects in mice with CUS-induced depression, reverses behavioral deficits, and normalizes the ERK/mTOR/VGF/BDNF signaling pathway in the hippocampus and prefrontal cortex (PFC); in contrast, Rapastinel (0.5 mg/kg; intravenous injection, once daily for 3 consecutive days) shows no activity^[1].
A single intravenous administration of Rapastinel (3 mg/kg) produces sustained antidepressant-like and anxiolytic-like effects in male Sprague-Dawley rats for at least 1 week, as evidenced by significant changes in ultrasonic vocalizations, time spent in the central zone of the open field test, and immobility time in the Porsolt forced swim test. It also induces sustained cognitive-enhancing effects, as reflected by improved behavioral performance of rats in spontaneous alternation, positive affective learning, Morris water maze, and contextual fear extinction tests^[3].
Rapastinel (1 mg/kg; subcutaneous injection; twice daily; administered for 3 or 5 days) reverses subchronic Phencyclidine-induced novel object recognition (NOR) impairment for at least 9 or 10 weeks, respectively, whereas Rapastinel (1 mg/kg; subcutaneous injection; 30 minutes in advance; single dose) only transiently reverses NOR function when the test interval is 24 hours^[4].
Rapastinel (10-30 mg/kg; subcutaneous injection; single administration) produces rapid and sustained antidepressant-like effects in rats, corresponding to concentrations of approximately 30 nM and ~100 nM in the medial prefrontal cortex (mPFC), respectively^[5].