Rapastinel () (former developmental code name GLYX-13) is a novel antidepressant that was under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant depression.
Clinical development
On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.
As of 2015, the drug had completed phase II clinical development for this indication and achieved proof of concept as a rapid-acting antidepressant by demonstrating reduced depressive symptoms at days 1 through 7, as assessed by the HAM-D, without eliciting psychotomimetic or other significant side effects.
On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.
On March 6, 2019, Allergan announced rapastinel failed to differentiate from placebo during phase III trials.
Pharmacology
Rapastinel binds to a novel and unique domain on the NMDA receptor complex that is distinct from the
glycine co-agonist binding site.
Rapastinel exhibits a biphasic dose response in vitro.
At therapeutically relevant concentrations, rapastinel enhances glutamate-mediated NMDA receptor activity, independent of glycine co-agonism, and enhances the magnitude of NMDAR-mediated synaptic plasticity at excitatory synapses in the mPFC.
Positive modulation of NMDA receptors by rapastinel produces antidepressant effects that are convergent with the NMDA receptor antagonist
ketamine, however, rapastinel has no ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms.
Preclinical research
In addition to its rapid and sustained antidepressant effects, rapastinel has been shown to
nootropic in both young adult and learning-impaired, aging
animal model.
It has been shown to increase Schaffer collateral-CA1 long-term potentiation
in vitro. In concert with a learning task, rapastinel has also been shown to elevate
gene expression of
hippocampus NR1, a subunit of the NMDA receptor, in three-month-old rats.
effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and
dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions.
History
Rapastinel was originally invented by Joseph Moskal, the co-founder of Naurex, via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.
See also
-
List of investigational antidepressants
External links
