The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant

Autor: Joseph R. Moskal, M. Amin Khan, John F. Disterhoft, Patric K. Stanton, Ronald M. Burch, Roger A. Kroes, Jeffrey Burgdorf
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Long-Term Potentiation
Drug Evaluation
Preclinical
rapid acting
Antidepressant
GLYX-13
Pharmacology
Receptors
N-Methyl-D-Aspartate
Article
03 medical and health sciences
0302 clinical medicine
Memory
Neuroplasticity
Metaplasticity
Rapastinel
Animals
Pharmacology (medical)
Prefrontal cortex
Maze Learning
Swimming
Neuronal Plasticity
major depressive disorder
Dose-Response Relationship
Drug
Depression
Dentate gyrus
Age Factors
Long-term potentiation
General Medicine
NMDA receptor
Antidepressive Agents
glycine site
Rats
Psychiatry and Mental health
Disease Models
Animal
030104 developmental biology
Neurology
Synaptic plasticity
Synapses
Exploratory Behavior
rapastinel
Neurology (clinical)
Vocalization
Animal
Psychology
Neuroscience
Oligopeptides
030217 neurology & neurosurgery
Zdroj: Current Neuropharmacology
ISSN: 1875-6190
1570-159X
Popis: 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.
Databáze: OpenAIRE
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