Mechanisms of action of CHF3381 in the forebrain

Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly −80% of the NMDA‐evoked current, with EC 50 of approximately 5 μ M . This effect was selective, reversible, use‐dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. CHF3381 also inhibited voltage‐gated Na + currents in an apparently voltage‐dependent manner. However, this effect could be obtained only at relatively high concentrations (100 μ M ). Consistent with the mild effects on voltage‐gated Na + channels, CHF3381 (100 μ M ) failed to affect electrical stimulation‐evoked glutamate overflow in hippocampal slices. In contrast, the anti‐convulsant agent and Na + channel blocker lamotrigine (100 μ M ) inhibited stimulation‐evoked glutamate overflow by approximately 50%. CHF3381 reduced kindled seizure‐induced c‐ fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo . The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation.British Journal of Pharmacology (2003) 139 , 1333–1341. doi: 10.1038/sj.bjp.0705381