Ifenprodil and SL 82.0715 as cerebral antiischemic agents. III. Evidence for antagonistic effects at the polyamine modulatory site within the N-methyl-D-aspartate receptor complex.
Ifenprodil and SL 82.0715 are noncompetitive N-methyl-D-aspartate (NMDA) antagonists whose inhibitory actions are not explained by antagonistic effects at any of the three commonly recognized 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 microM) increase the binding of [3H]1-[1-(2-thienyl)cyclohexyl] piperidine to washed rat forebrain membranes in the presence of glutamate (10 microM). This effect is antagonized by ifenprodil and SL 82.0715 (0.1-10 microM) at concentrations which do not displace [3H]1-(2-thienyl)cyclohexyl] piperidine in the absence of added polyamine. Spermine and spermidine (up to 100 microM) 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 microM) antagonize this effect; ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate) or 7-chlorokynurenate (100 microM) are ineffective. In immature rat cerebellar slices, spermine and spermidine (10-1000 microM) potentiate the maximal effects of NMDA (80-160 microM) on cyclic GMP production. Spermine (100-1000 microM) reverses the antagonistic effects of ifenprodil (0.15-50 microM) but not of ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine acid or kynurenate on the NMDA receptor-mediated increase in cyclic GMP levels. Ifenprodil (0.01-1 microM) potently but only partially antagonizes the depolarizing effects of NMDA (10 microM) on the immature rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)
Carter
C J
CJ
Synthélabo Recherche, Biology Department, Bagneux, France.
Lloyd
K G
KG
Zivkovic
B
B
Scatton
B
B
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004347:Drug Interactions; D005260:Female; D005998:Glycine / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D013095:Spermidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013096:Spermine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D013096:Spermine; D001224:Aspartic Acid; D016202:N-Methylaspartate; C012058:tenocyclidine; D010622:Phencyclidine; C010739:ifenprodil; D005998:Glycine; D013095:Spermidine; C058083:eliprodil