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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Falk Center for Molecular Therapeutics, Northwestern University, Department of Biomedical Engineering, 1801 Maple Ave., Suite 4300, Evanston, IL, 60201, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Burgdorf
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
authors.forename: Roger A
authors.initials: RA
authors.lastname: Kroes
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Burch
authors.forename: M Amin
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000367:Age Factors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005106:Exploratory Behavior / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013550:Swimming; D013569:Synapses / Q000187:drug effects / Q000648:ultrastructure; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; C507283:GLYX-13 peptide