Rapastinel Explained

Rapastinel (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.[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.

Clinical development

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]

Preclinical development

Rapastinel was originally invented by Joseph Moskal, the co-founder of Naurex, via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.[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.[12] Rapastinel exhibits a biphasic dose response in vitro.[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. 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 expression of hippocampal 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]

See also

External links

Notes and References

  1. Henter ID, Park LT, Zarate CA . Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status . CNS Drugs . 35 . 5 . 527–543 . May 2021 . 33904154 . 8201267 . 10.1007/s40263-021-00816-x .
  2. Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM, Khan MA . The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant . Current Neuropharmacology . 15 . 1 . 47–56 . 2016 . 26997507 . 5327451 . 10.2174/1570159x14666160321122703 .
  3. Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, Miry O, Kehr J, Stanton PK, Gross AL, Burgdorf JS, Kroes RA, Moskal JR . 6 . Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects . The International Journal of Neuropsychopharmacology . 22 . 3 . 247–259 . March 2019 . 30544218 . 6403082 . 10.1093/ijnp/pyy101 .
  4. FDA Grants Fast Track Designation to Naurex's Rapid-Acting Novel Antidepressant GLYX-13 . www.prnewswire.com .
  5. Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM . 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 . March 2015 . 25782764 . 10.1097/01.pra.0000462606.17725.93 . 36800194 .
  6. Allergan's Rapastinel Receives FDA Breakthrough Therapy Designation for Adjunctive Treatment of Major Depressive Disorder (MDD) . 2022-05-13 . www.prnewswire.com . en.
  7. Web site: Allergan Announces Phase 3 Results for Rapastinel as an Adjunctive Treatment of Major Depressive Disorder (MDD). https://web.archive.org/web/20230622044047/https://news.abbvie.com/news/allergan-press-releases/allergan-announces-phase-3-results-for-rapastinel-as-an-adjunctive-treatment-major-depressive-disorder-mdd.htm. June 22, 2023. live.
  8. Web site: Home - Gate Neurosciences . 2022-05-13 . en-US . 2023-09-05 . https://web.archive.org/web/20230905072934/https://www.gateneuro.com/ . live .
  9. Haring R, Stanton PK, Scheideler MA, Moskal JR . 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 . July 1991 . 1828831 . 10.1111/j.1471-4159.1991.tb02131.x . 37941813 .
  10. Moskal JR, Kuo AG, Weiss C, Wood PL, O'Connor Hanson A, Kelso S, Harris RB, Disterhoft JF . 6 . GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator . Neuropharmacology . 49 . 7 . 1077–1087 . December 2005 . 16051282 . 10.1016/j.neuropharm.2005.06.006 . 7372648 .
  11. Burgdorf J, Zhang XL, Weiss C, Matthews E, Disterhoft JF, Stanton PK, Moskal JR . The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats . Neurobiology of Aging . 32 . 4 . 698–706 . April 2011 . 19446371 . 3035742 . 10.1016/j.neurobiolaging.2009.04.012 .
  12. Pothula S, Liu RJ, Wu M, Sliby AN, Picciotto MR, Banerjee P, Duman RS . Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons . Neuropsychopharmacology . 46 . 4 . 799–808 . March 2021 . 33059355 . 8027594 . 10.1038/s41386-020-00882-7 .
  13. Zhang XL, Sullivan JA, Moskal JR, Stanton PK . A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus . Neuropharmacology . 55 . 7 . 1238–1250 . December 2008 . 18796308 . 2661239 . 10.1016/j.neuropharm.2008.08.018 .
  14. Pothula S, Kato T, Liu RJ, Wu M, Gerhard D, Shinohara R, Sliby AN, Chowdhury GM, Behar KL, Sanacora G, Banerjee P, Duman RS . 6 . Cell-type specific modulation of NMDA receptors triggers antidepressant actions . Molecular Psychiatry . 26 . 9 . 5097–5111 . September 2021 . 32488125 . 10.1038/s41380-020-0796-3 . 219175373 .
  15. Kato T, Duman RS . Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: Convergent mechanisms . Pharmacology, Biochemistry, and Behavior . 188 . 172827 . January 2020 . 31733218 . 10.1016/j.pbb.2019.172827 . 207976034 .
  16. Burgdorf J, Zhang XL, Weiss C, Matthews E, Disterhoft JF, Stanton PK, Moskal JR . The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats . Neurobiology of Aging . 32 . 4 . 698–706 . April 2011 . 19446371 . 3035742 . 10.1016/j.neurobiolaging.2009.04.012 .
  17. Moskal JR, Kuo AG, Weiss C, Wood PL, O'Connor Hanson A, Kelso S, Harris RB, Disterhoft JF . 6 . GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator . Neuropharmacology . 49 . 7 . 1077–1087 . December 2005 . 16051282 . 10.1016/j.neuropharm.2005.06.006 . 7372648 .
  18. Stanton PK, Potter PE, Aguilar J, Decandia M, Moskal JR . Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13 . NeuroReport . 20 . 13 . 1193–1197 . August 2009 . 19623090 . 10.1097/WNR.0b013e32832f5130 . 6269255 .

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