Preprint Watch 2026-05-20: 1 Clinical Failures Flagged for GRIN2B | Claidex

Q: Why was this GRIN2B preprint flagged?

1 prior Claidex failure claim matched the target-disease mechanism. This preprint reports a mechanistic claim about GRIN2B that is consistent with the documented Claidex failures mij821-onfasprodil-mdd-suicidality-efficacy-failure. The reported observations should be read against the field-level evidence that targeting GRIN2B alone has produced limited durable activity in the indications studied to date.

Claidex Preprint Watch

doi:10.1101/2025.10.22.683915

Preprint WatchModerateMay 20th, 2026

Expression and localization of NMDA receptor GluN2 subunits in dorsal horn pain circuits across sex, species, and late postnatal development

Griffiths, K. M.; Armstrong, J.; Martin, N.; Murray Lawson, C.; Oneil, E.; David, L. S.; Temi, S.; Parnell, J.; Rudyk, C.; Bursey, J.; Krajewski, J. L.; McDermott, J. S.; Dedek, A.; Levine, A. J.; Li, B.; Tsai, E. C.; Hildebrand, M. E.

Expression and localization of NMDA receptor GluN2 subunits in dorsal horn pain circuits across sex, species, and late postnatal development

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports a mechanistic claim about GRIN2B that is consistent with the documented Claidex failures mij821-onfasprodil-mdd-suicidality-efficacy-failure. The reported observations should be read against the field-level evidence that targeting GRIN2B alone has produced limited durable activity in the indications studied to date.

Abstract excerpt

Despite being essential mediators of pain processing, the molecular identity of N-methyl-D-aspartate receptor (NMDAR) subtypes in nociceptive dorsal horn circuits is poorly understood, especially between sexes and in humans. Given the importance of GluN2 subunits in shaping NMDAR function and plasticity, we investigated the expression and localization of specific GluN2 NMDAR variants in the dorsal horn of viable spinal cord tissue from male and female rodents and human organ donors. Analysis of single-cell/nuclei sequencing datasets and quantitative reverse transcriptase polymerase chain reactions (qRT-PCR) revealed that the GluN2A (GRIN2A) and GluN2B (GRIN2B) subunits are robustly expressed in dorsal horn neurons of mice, rats and humans, with moderate expression of GluN2D (GRIN2D). Immunohistochemistry (IHC) with antigen retrieval demonstrated that GluN2A, GluN2B, and GluN2D proteins are all preferentially localized to the superficial dorsal horn of both adult rats and humans, which is conserved between males and females. Surprisingly, we found that these GluN2 NMDAR subunits are enriched in the lateral superficial dorsal horn in rats but not in humans, while presynaptic and neuronal markers are symmetrically distributed across the rat mediolateral axis. A dramatic shift in localization of GluN2A to the lateral superficial dorsal horn was observed across later postnatal development (PD21-PD90) in both male and female rats, with a corresponding change in synaptic NMDAR currents. This discovery of changes in NMDAR subunit distribution during maturation and between species will shed light on the physiological roles of NMDARs and their potential as therapeutic targets for pain.

Matching Claidex post-mortems

1 of 1 indexed

May 19, 2026Onfasprodil (MIJ821) in MDD with suicidal ideation: an NR2B-selective NMDA antagonist that worked for TRD but matched placebo at 24 hoursOnfasprodil (MIJ821)EfficacyMRS 33

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.