On March 3, 2014, the U.S. FDA grantedFast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[4] As of 2015, the drug had completedphase II clinical development for this indication and achievedproof of concept as a rapid-acting antidepressant by demonstrating reduced depressive symptoms at days 1 through 7, as assessed by theHAM-D, without eliciting psychotomimetic or other significant side effects.[5] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had receivedBreakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.[6]
On March 6, 2019, Allergan announced rapastinel failed to differentiate from placebo during phase III trials.[7] Early successful clinical studies of rapastinel in depression spurred the development of next-generation compounds with similar mechanisms of action includingapimostinel (GATE-202, NRX-1074), a 2nd generationanalog with improvedpotency, andzelquistinel (GATE-251, AGN-241751), a 3rd generation small molecule with improved potency and high oral bioavailability.[8]
Rapastinel binds to a novel and unique domain on the NMDA receptor complex that is distinct from theglycine co-agonist binding site.[3][9] Rapastinel exhibits a biphasic dose response in vitro.[3][10] At therapeutically relevant concentrations, rapastinel enhances glutamate-mediated NMDA receptor activity, independent of glycine co-agonism, and enhances the magnitude of NMDAR-mediated synaptic plasticity atexcitatory synapses in themPFC.[3][10] Positive modulation of NMDA receptors by rapastinel produces antidepressant effects that are convergent with theNMDA receptor antagonistketamine, however, rapastinel has no ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms.[11][12]
^Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM (March 2015). "Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent".Journal of Psychiatric Practice.21 (2):140–149.doi:10.1097/01.pra.0000462606.17725.93.PMID25782764.S2CID36800194.
^Pothula S, Kato T, Liu RJ, Wu M, Gerhard D, Shinohara R, et al. (September 2021). "Cell-type specific modulation of NMDA receptors triggers antidepressant actions".Molecular Psychiatry.26 (9):5097–5111.doi:10.1038/s41380-020-0796-3.PMID32488125.S2CID219175373.
^Kato T, Duman RS (January 2020). "Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: Convergent mechanisms".Pharmacology, Biochemistry, and Behavior.188 172827.doi:10.1016/j.pbb.2019.172827.PMID31733218.S2CID207976034.
^Moskal JR, Kuo AG, Weiss C, Wood PL, O'Connor Hanson A, Kelso S, et al. (December 2005). "GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator".Neuropharmacology.49 (7):1077–1087.doi:10.1016/j.neuropharm.2005.06.006.PMID16051282.S2CID7372648.
^Stanton PK, Potter PE, Aguilar J, Decandia M, Moskal JR (August 2009). "Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13".NeuroReport.20 (13):1193–1197.doi:10.1097/WNR.0b013e32832f5130.PMID19623090.S2CID6269255.
^Haring R, Stanton PK, Scheideler MA, Moskal JR (July 1991). "Glycine-like modulation of N-methyl-D-aspartate receptors by a monoclonal antibody that enhances long-term potentiation".Journal of Neurochemistry.57 (1):323–332.doi:10.1111/j.1471-4159.1991.tb02131.x.PMID1828831.S2CID37941813.
^Moskal JR, Kuo AG, Weiss C, Wood PL, O'Connor Hanson A, Kelso S, et al. (December 2005). "GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator".Neuropharmacology.49 (7):1077–1087.doi:10.1016/j.neuropharm.2005.06.006.PMID16051282.S2CID7372648.
