The development of rapastinel (formerly GLYX-13); a rapid acting and long lasting antidepressant

Joseph R. Moskal*, Jeffrey S. Burgdorf, Patric K. Stanton, Roger A. Kroes, John F. Disterhoft, Ronald M. Burch, M. Amin Khan

*Corresponding author for this work

Research output: Contribution to journalReview article

32 Citations (Scopus)

Abstract

Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined. Results: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel’s rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing. Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalCurrent neuropharmacology
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2017

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Antidepressive Agents
Nootropic Agents
Threonine
N-Methyl-D-Aspartate Receptors
Proline
Learning
Learned Helplessness
Dendritic Spines
Neuronal Plasticity
Aptitude
Dentate Gyrus
Prefrontal Cortex
Amides
Glycine
Amino Acid Sequence
Animal Models
Monoclonal Antibodies
Clinical Trials
Pharmacology
Light

Keywords

  • Antidepressant
  • GLYX-13
  • Glycine site
  • Major depressive disorder
  • NMDA receptor
  • Rapastinel
  • Rapid acting

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

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title = "The development of rapastinel (formerly GLYX-13); a rapid acting and long lasting antidepressant",
abstract = "Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined. Results: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel’s rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing. Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.",
keywords = "Antidepressant, GLYX-13, Glycine site, Major depressive disorder, NMDA receptor, Rapastinel, Rapid acting",
author = "Moskal, {Joseph R.} and Burgdorf, {Jeffrey S.} and Stanton, {Patric K.} and Kroes, {Roger A.} and Disterhoft, {John F.} and Burch, {Ronald M.} and Khan, {M. Amin}",
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The development of rapastinel (formerly GLYX-13); a rapid acting and long lasting antidepressant. / Moskal, Joseph R.; Burgdorf, Jeffrey S.; Stanton, Patric K.; Kroes, Roger A.; Disterhoft, John F.; Burch, Ronald M.; Khan, M. Amin.

In: Current neuropharmacology, Vol. 15, No. 1, 01.01.2017, p. 47-56.

Research output: Contribution to journalReview article

TY - JOUR

T1 - The development of rapastinel (formerly GLYX-13); a rapid acting and long lasting antidepressant

AU - Moskal, Joseph R.

AU - Burgdorf, Jeffrey S.

AU - Stanton, Patric K.

AU - Kroes, Roger A.

AU - Disterhoft, John F.

AU - Burch, Ronald M.

AU - Khan, M. Amin

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined. Results: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel’s rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing. Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.

AB - Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined. Results: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel’s rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing. Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.

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