GLYX-13

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GLYX-13
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
Pregnancy cat. ? (US)
Legal status Investigational New Drug
Identifiers
CAS number 117928-94-6
ATC code None
Chemical data
Formula C18H31N5O6 
Mol. mass 413.47 g/mol

GLYX-13 is a selective, weak partial agonist of the glycine site of the NMDA receptor (IA ≈ 25%).[1] It has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.[2] GLYX-13, a tetrapeptide (H-Thr-Pro-Pro-Thr-NH2), readily crosses the blood brain barrier, and has been shown to increase Schaffer collateral-CA1 long-term potentiation in vitro. In concert with a learning task it has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in 3-month-old rats.[3] 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.[4]

Additionally, GLYX-13 has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while GLYX-13 and other glycine subunit ligands are able to elicit analgesia at sub-ataxic doses.[5]

Clinical Trials[edit]

Preclinical data indicates that GLYX-13 has a therapeutic index of 500 or more, onset within 20 minutes of administration, and produces antidepressant-like effects lasting approximately two weeks following administration. Currently under development by Naurex Inc, the compound recently completed phase II trials as a treatment for those resistant or non-responsive to traditional antidepressants.[6] On March 3, 2014 the FDA granted Fast Track designation to the investigation of GLYX-13 as an adjunctive therapy in major depressive disorder.[7]

See also[edit]

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. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ ClinicalTrials.gov NCT01234558 Single IV Dose of GLYX-13 in Patients With Treatment-Resistant Depression
  7. ^ 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

External links[edit]