Rapastinel (GLYX-13) is a novel NMDA receptor modulator. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. 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. 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. From the di-pyrrolidine core of Rapastineal, spiro-b-lactams were synthesized and showed many of the properties of Rapastinel, thus providing the foundation for the creation of a fully synthetic medicinal chemistry program with novel molecules that show differential receptor subtype binding properties. These data suggest that Rapastinel has significant effects on metaplasticity processes that may help explain the rapid acting and long lasting beneficial effects seen in clinical trials of treatment resistant depression and obsessive-compulsive subjects. Moreover, the new, fully synthetic, chemical platform should provide useful tools to further dissect the role of NMDA receptors in both normal and abnormal brain function.