Neomycin Is an Agonist at a Polyamine Site on the N-Methyl-D-Aspartate Receptor

Neomycin appears as a full agonist and spermidine as a partial agonist at the site where polyamines enhance 1-1-(2-thienyl)cyclohexyl]3H]piperidine (3H]TCP) binding on the N-methyl-D-aspartate (NMDA) receptor. Other aminoglycosides also enhance 3H]TCP binding with efficacies roughly proportional to the number of primary amine groups. The polyamine antagonists ifenprodil and arcaine inhibit enhancement of 3H]TCP binding by spermidine or neomycin. The inhibition of 3H]TCP binding by arcaine is apparently competitively reduced by neomycin and spermidine, supporting a common site. Diethylenetriamine (previously described as a polyamine antagonist) may be a partial agonist. Enhancement by neomycin or spermidine is not additive to that of Mg2+, consistent with competition of Mg2+ and spermidine or neomycin at the site where these compounds enhance 3H]TCP binding. Polyamines also enhance the binding of the competitive antagonist 2-(2-carboxypiperazin-4-yl)3H]propyl-1-phosphonic acid (3H]CPP). Neomycin, which does not enhance 3H]CPP binding, inhibits the enhancement by spermidine. That this site is distinct from the site where spermidine and neomycin increase 3H]TCP binding is supported by different pharmacology. Arcaine and diethylenetriamine do not inhibit spermidine enhancement of 3H]CPP binding. Mg2+ also does not compete with the spermidine enhancement of 3H]CPP binding. Ifenprodil inhibits the spermidine enhancement of 3H]CPP binding. The data suggest two or more polyamine sites, with arcaine selective for the site that enhances 3H]TCP binding. Neomycin is an agonist at one polyamine site and antagonist to the second.