IFENPRODIL AND SL-82.0715 AS CEREBRAL ANTIISCHEMIC AGENTS .3. EVIDENCE FOR ANTAGONISTIC EFFECTS AT THE POLYAMINE MODULATORY SITE WITHIN THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX

  • 1 May 1990
    • journal article
    • research article
    • Vol. 253  (2) , 475-482
Abstract
Ifenprodil and SL 82.0715 are noncompetitive N-methyl-D-aspartate (NMDA) antagonists whose inhibitory actions are not explained by antagonistic effects at nay of the three commonly recongnized sites within the NMDA receptor complex (recognition, channel and modulatory glycine sites). We presently show that ifenprodil and SL 82.0715 antagonize the effects of NMDA via a selective action at the recently described polyamine modulatory site. Spermine and spermidine (0.5 - 100 .mu.M) increase the binding of [3H]1-[1-(2-thienyl)cyclohexyl] piperidine to washed rat forebrain membranes in the presnce of glutamate (10 .mu.M). This effect is antagonized by ifenprodil and SL 82.0715 (0.1 - 1.0 .mu.M) at concentrations which do not displace [3H]1-[1-(2-thienyl)cyclohexyl] piperidine in the absence of added polyamine. Spermine and spermidine (up to 100 .mu.M) do not significantly alter the binding of [3H]glycine but increase the binding of the NMDA recognition site ligand [3H] (.+-.)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid. Ifenprodil and SL 82.0715 (0.1 - 10 .mu.M) antagonize this effect; ((+)-5-methyl-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-10 imine maleate) or 7-chlorokynurenate (100 .mu.M) are ineffective. In immature rat cerebellar slices, spermine and spermidine (10-1000 .mu.M) potentiate the maximal effects of NMDA (80-160 .mu.M) on cyclic GMP production. Spermine (100 - 1000 .mu.M) reverses the antagonistic effectrs of ifenprodil (0.15 - 50 .mu.M) but not of ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate), (.+-.)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid or kynurenate on the NDMA receptor-median increase in cyclic GMP levels. Ifenprodil (0.01 -1 .mu.M) potently but only partially antagonizes the depolarizing effects of NMDA (10 .mu.M) on the immature rat spinal cord. Spermidine or spermine (100 .mu.M) has no effect on responses to low perfusing concentrations of NMDA (2.5 - 10 .mu.M) but displaces the ifenprodil inhibition curve to the right; in addition, ifenprodil exerts a greter inhibitory effect in the presence of either polyamine. The data suggest that ifenprodil and SL 82.0715 antagonize the effects of NMDA via a selective interaction with a polyamine-sensitive regulatory site on the NMDA receptors.

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