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| Other names | GLYX-13; BV-102 |
| Routes of administration | Intravenous |
| Drug class | Selective NMDA receptor modulator |
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| Formula | C18H31N5O6 |
| Molar mass | 413.475 g·mol−1 |
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Rapastinel (INNTooltip International Nonproprietary Name) (former developmental code name GLYX-13) is a novel antidepressant that was under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant depression.[1][2] It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide that acts as a novel and selective modulator of the NMDA receptor.[1][2][3] The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to enhance NMDA receptor-mediated signal transduction and synaptic plasticity.[1][2][3]
On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[4] As of 2015, the drug had completed phase II clinical development for this indication and achieved proof of concept as a rapid-acting antidepressant by demonstrating reduced depressive symptoms at days 1 through 7, as assessed by the HAM-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 received Breakthrough 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 including apimostinel (GATE-202, NRX-1074), a 2nd generation analog with improved potency, and zelquistinel (GATE-251, AGN-241751), a 3rd generation small molecule with improved potency and high oral bioavailability.[8]
Rapastinel was originally invented by Joseph Moskal, the co-founder of Naurex, via structural modificationofB6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.[2][9][10][11] Rapastinel binds to a novel and unique domain on the NMDA receptor complex that is distinct from the glycine co-agonist binding site.[3][12] Rapastinel exhibits a biphasic dose response in vitro.[3][13] 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 at excitatory synapses in the mPFC.[3][13] Positive modulation of NMDA receptors by rapastinel produces antidepressant effects that are convergent with the NMDA receptor antagonist ketamine, however, rapastinel has no ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms.[14][15]
In addition to its rapid and sustained antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.[16] It has been shown to increase Schaffer collateral-CA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expressionofhippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats.[17] Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions.[18]
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