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.