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.
Department of Pharmacology, ICI Americas, Inc., Wilmington, DE 19897.
L M
LM
Pullan
R J
RJ
Stumpo
R J
RJ
Powel
K A
KA
Paschetto
M
M
Britt
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009355:Neomycin / Q000494:pharmacology*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011073:Polyamines / Q000032:analysis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D013095:Spermidine / Q000494:pharmacology; D013570:Synaptic Membranes / Q000648:ultrastructure; D014316:Tritium
D000317:Adrenergic alpha-Antagonists; D001645:Biguanides; D010879:Piperazines; D010880:Piperidines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C005391:diethylenetriamine; D014316:Tritium; C006624:arcaine; C012058:tenocyclidine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D009355:Neomycin; D008274:Magnesium; D010622:Phencyclidine; C010739:ifenprodil; D013095:Spermidine