Rapastinel

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Rapastinel
GLYX-13 structure.png
GLYX-133Dan.gif
Systematic (IUPAC) name
(S)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-1-[(S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide
Clinical data
  • US: N (Not classified yet)
  • Investigational New Drug
Identifiers
117928-94-6
None
ChemSpider 25069944
Chemical data
Formula C18H31N5O6
413.47 g/mol

Rapastinel (INN) (code name GLYX-13) is a selective weak partial agonist of the glycine site of the NMDA receptor (IA ≈ 25%) which is under development by Naurex as an adjunctive therapy for treatment-resistant depression.[1] It is an amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) which rapidly crosses the blood-brain-barrier, but is not active orally.[2] On March 3, 2014 the FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[3] As of December 2014, the drug has completed phase IIb clinical trials for this indication.[4] Phase III clinical trials will be starting in 2015.[4]

In addition to its antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.[5] 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 3-month-old rats.[6] 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.[7] Additionally, rapastinel has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while rapastinel and other glycine subunit ligands are able to elicit analgesia at sub-ataxic doses.[8]

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References[edit]

  1. ^ Hashimoto K, Malchow B, Falkai P, Schmitt A (August 2013). "Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders". Eur Arch Psychiatry Clin Neurosci 263 (5): 367–77. doi:10.1007/s00406-013-0399-y. PMID 23455590. 
  2. ^ http://webcache.googleusercontent.com/search?q=cache:I8h0z6_2oscJ:adisinsight.springer.com/drugs/800031281+&cd=2&hl=en&ct=clnk&gl=us
  3. ^ FDA Grants Fast Track Designation to Naurex's Rapid-Acting Novel Antidepressant GLYX-13 http://www.prnewswire.com/news-releases/fda-grants-fast-track-designation-to-naurexs-rapid-acting-novel-antidepressant-glyx-13-248174561.html
  4. ^ a b http://naurex.com/wp-content/uploads/2014/12/Naurex_P2b_Data_Press_Release_FINAL_Approved.pdf
  5. ^ Burgdorf, Jeffrey; Zhang, Xiao-lei; Weiss, Craig; Matthews, Elizabeth; Disterhoft, John F.; Stanton, Patric K.; Moskal, Joseph R. (2011). "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. doi:10.1016/j.neurobiolaging.2009.04.012. PMC 3035742. PMID 19446371. 
  6. ^ Moskal, Joseph R.; Kuo, Amy G.; Weiss, Craig; Wood, Paul L.; O'Connor Hanson, Amy; Kelso, Stephen; Harris, Robert B.; Disterhoft, John F. (2005). "GLYX-13: A monoclonal antibody-derived peptide that acts as an N-methyl-d-aspartate receptor modulator". Neuropharmacology 49 (7): 1077–87. doi:10.1016/j.neuropharm.2005.06.006. PMID 16051282. 
  7. ^ Stanton, Patric K.; Potter, Pamela E.; Aguilar, Jennifer; Decandia, Maria; Moskal, Joseph R. (2009). "Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13". NeuroReport 20 (13): 1193–7. doi:10.1097/WNR.0b013e32832f5130. PMID 19623090. 
  8. ^ Wood, Paul L.; Mahmood, Siddique A.; Moskal, Joseph R. (2008). "Antinociceptive action of GLYX-13: An N-methyl-D-aspartate receptor glycine site partial agonist". NeuroReport 19 (10): 1059–61. doi:10.1097/WNR.0b013e32830435c9. PMID 18580579. 

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