Molecular features associated with polyamine modulation of NMDA receptors

The effect of 1,3-diamines on basal and spermine-stimulated [3H]MK-801 binding was investigated. Systematic variations in the molecular parameters revealed that, in general, lipophilic 1,3-diamines inhibited and hydrophilic 1,3-diamines enhanced [3H]MK-801 binding in the nominal absence of glutamate and glycine. Furthermore, 1,3-diamines which were highly monoprotonated at physiologic pH were more effective in modulating basal binding (at 100 microM 1,3-diamine) than analogues which were mostly diprotonated or unprotonated. Finally, the internuclear distance between the amino nitrogens and the extent of modulation of basal [3H]MK-801 binding were correlated. Similar, but more modest, effects were seen for spermine-enhanced [3H]MK-801 binding. These results are consistent with the existence of two polyamine binding sites associated with the NMDA receptor complex. One of the sites appears to preferentially recognize lipophilic substances while the other favors hydrophilic materials. Both sites appear to recognize polyamines with at least one charged (protonated) amino group and one uncharged amino group. The distance between amino groups is a determining factor as well.