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][H-3]piperidine ([H-3]TCP) binding on the N-methyl-D-aspartate (NMDA) receptor. Other aminoglycosides also enhance [H-3]TCP binding with efficacies roughly proportional to the number of primary amine groups. The polyamine antagonists ifenprodil and arcaine inhibit enhancement of [H-3]TCP binding by spermidine or neomycin. The inhibition of [H-3]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 [H-3]TCP binding. Polyamines also enhance the binding of the competitive antagonist 2 - (2 - carboxypiperazin - 4 - yl)[H-3]propyl - 1 - phosphonic acid ([H-3]CPP). Neomycin, which does not enhance [H-3]CPP binding, inhibits the enhancement by spermidine. That this site is distinct from the site where spermidine and neomycin increase [H-3]TCP binding is supported by different pharmacology. Arcaine and diethylenetriamine do not inhibit spermidine enhancement of [H-3]CPP binding. Mg2+ also does not compete with the spermidine enhancement of [H-3]CPP binding. Ifenprodil inhibits the spermidine enhancement of [H-3]CPP binding. The data suggest two or more polyamine sites, with arcaine selective for the site that enhances [H-3]TCP binding. Neomycin is an agonist at one polyamine site and an antagonist to the second.