Pharmacological activity of a new ligand binding at the histamine site of the NMDA receptor in rodents.

NMDA receptor ligands have been the target of intensive research for the treatment of psychotic and various central nervous system disorders. Substantial evidence suggests that N-methyl-D-aspartate receptor hypofunction and its downregulation contribute to schizophrenia pathophysiology. The NMDA receptor histamine site (NMDA(HA)R) is a new potential target of NMDA receptor modulation, and ligands for this site have been developed. In this study, we used various models to assess NMDA receptor activity and antipsychotic potential in rodents, highlighting the most potent ligand of NMDA (HA)R: FUBn203, a partial agonist with nanomolar affinity in vitro. FUBn293 modulated MK 801 binding in vitro with an ED50 of 1 mg/kg. FUBn293 dose-dependently decreased MK-801-induced hyperlocomotion (ED50 = 3.8 mg/kg i. p). FUBn293 (10 mg/kg i. p.) significantly reduced the conditioned active avoidance test response and suppressed the MK-801-induced prepulse inhibition deficit. According to these findings, NMDA (HA)R agonists may offer a novel class of antipsychotic medications for the treatment of some aspects of schizophrenia and other neurological or psychiatric disorders.