A novel mechanism of activity‐dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones.

Ifenprodil is a selective, atypical non-competitive antagonist of NMDA receptors that contain the NR2B subunit with an undefined mechanism of action. Ifenprodil is neuroprotective in in vivo models of cerebral ischaemia but lacks many of the undesirable side-effects associated with NMDA antagonist. 2. Using whole-cell voltage-clamp recordings, we have studied the mechanism of inhibition of NMDA-evoked currents by ifenprodil in rat cultured cortical neurones in the presence of saturating concentrations of glycine. 3. Ifenprodil antagonized NMDA receptors in an activity-dependent manner, whilst also increasing the receptor affinity for glutamate recognition-site agonists. Ifenprodil inhibition curves against 10 and 100 microM NMDA-evoked currents yielded IC50 values of 0.88 and 0.17 microM, respectively. Thus, the apparent affinity of ifenprodil for the NMDA receptor is increased in an NMDA concentration-dependent manner. 4. Currents evoked by 0.3 and 1 microM NMDA were potentiated to approximately 200% of control levels in the presence of 3 microM ifenprodil. Thus, with increasing concentration of NMDA the effect of ifenprodil on NMDA-evoked currents changed from one of potentiation to one of increasing inhibition. 5. These results are predicted by a reaction scheme in which ifenprodil exhibits a 39- and 50-fold higher affinity for the agonist-bound activated and desensitized states of the NMDA receptor, respectively, relative to the resting, agonist-unbound state. Furthermore, ifenprodil binding to the NMDA receptor results in a 6-fold higher affinity for glutamate site agonists. 6. This represents a novel mechanism of NMDA receptor antagonism that, together with the subunit selectivity, probably contributes to the attractive neuropharmacological profile of this and related compounds.