Ifenprodil and SL 82.0715 antagonize the effects of NMDA via a polyamine-sensitive modulatory site

Abstract

Ifenprodil and SL 82.0715 are non-competitive NMDA antagonists with cytoprotective ability in animal models of cerebral ischaemia. However, their mechanism of action in relation to the various sites on the NMDA receptor (recognition, channel or glycine) is obscure. A further modulatory site on the NMDA receptor, responsive to spermine and spermidine has recently been proposed. In this study, we have investigated the possible interaction of ifenprodil and SL 82.0715 with this polyamine modulatory site. The polyamines spermine and spermidine (0.1–100 μM) increase the binding of ³H-CPP and ³H-TCP to rat brain membranes. These effects are antagonized by micromolar concentrations of ifenprodil and SL 82.0715. In contrast, MK-801 or 7-chlorokynurenate had no effect on the polyamine-induced increase in ³H-CPP binding. Spermine and spermidine (10–1000 μM) also potentiate the effects of NMDA on cyclic GMP production in immature rat cerebellar slices (maximal increase 400 and 160%, respectively). Neither polyamine stimulated cyclic GMP production in the absence of NMDA. Spermine (100 μM and 1 mM) reversed the inhibitory effects of ifenprodil but not of MK-801, CPP or kynurenate on this NMDA receptor mediated response. The present data support the existence of a polyamine modulatory site within the NMDA receptor complex, and suggest that ifenprodil and SL 82.0715 are antagonists at this site.