Studies show efficacy of rapastinel for treatment-resistant depression

Studies presented at the Society for Neuroscience Annual Meeting explored the antidepressant effects of rapastinel, an N-methyl-D-aspartate subtype of glutamate receptor modulator with characteristics of a glycine site partial agonist, currently in phase II clinical development for treatment-resistant depression.

Researchers used hippocampal slices to evaluate the potential of pharmacological modulation of N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) activity through the obligatory co-agonist binding site, its effect on modulation of the dissemination of cortical spreading depolarization and modulation of cortical spreading depolarization effects on dendritic spine morphology.

Researchers found that rapastinel prevented induction of cortical spreading depolarization at times and when doing so, significantly slowed the rate of dissemination.

In a subset of slices, primary cortical spreading depolarization triggered by “a focal puff of high [K+]” resulted in delayed, secondary cortical spreading depolarization that began at the border between pyramidal cell bodies and stratum oriens. Rapastinel blocked induction of these secondary cortical spreading depolarizations.

Cortical spreading depolarization passing through the CA1 stratum radiatum induced a rapid reaction of apical dendritic spines that reversed to an increase in spine volume after neuronal depolarization recovered. Rapastinel improved the rate and extent of return of dendritic spines to their original sizes and locations following cortical spreading depolarization.

“These data indicate that NMDAR modulation to renormalize activity may be an effective new treatment strategy for suppression or amelioration of the contribution of [cortical spreading depolarization] to short- and long-term symptoms of migraine attacks, as well as [cortical spreading depolarization] following stroke and traumatic brain injury,” the researchers wrote.

A second study evaluated the in vitro characteristics of rapastinel by measuring functional glycine site agonist effects using [3H]MK-801 potentiation assays in membrane extracts from rat cortex and human NR2 subtype-expression Human Embryonic Kidney 293 (HEK) cells.

In recombinant human NR2-expressing HEK cells, rapastinel demonstrated partial agonist activity at all four receptor subtypes: NR2A, NR2B, NR2C and NR2D.

Rapastinel also exhibited antagonist-like activity in hippocampal slices in the presence of glycine.

Rapastinel had no effect on glycine binding in cortical membranes and remained fully active in the presence of deoxycytidine kinase.

Point mutations in the glycine site did not affect the ability of rapastinel to modulate channel opening in any of the NMDAR subtypes.

Rapastinel did not affect the ability of glutamate, spermidine or ifenprodil to modulate NMDAR channel opening.

Further, molecular modeling in silico indicate a potential high affinity rapastinel binding site within the amino terminal domain of NR2B.

“These data suggest that rapastinel is an allosteric NMDAR modulator with glycinesite partial agonist properties attributable to binding to a novel site on the NMDAR,” the researchers concluded. – by Amanda Oldt

Reference:

Kroes RA, et al. Abstract 772.21/F15. Presented at: Society for Neuroscience Annual Meeting; Oct. 17-21, 2015; Chicago.

Zhang X-L, et al. Abstract 772.14/F8. Presented at: Society for Neuroscience Annual Meeting; Oct. 17-21, 2015; Chicago.

Disclosure: Kroes reports full or part-time employment/salary and ownership interest at Naurex, Inc. Zhang reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.