MOLECULAR-FEATURES ASSOCIATED WITH POLYAMINE MODULATION OF NMDA RECEPTORS

The effect of 1,3-diamines on basal and spermine-stimulated [H-3]MK-80 1 binding was investigated. Systematic variations in the molecular par ameters revealed that, in general, lipophilic 1,3-diamines inhibited a nd hydrophilic 1,3-diamines enhanced [H-3]MK-801 binding in the nomina l absence of glutamate and glycine. Furthermore, 1,3-diamines which we re highly monoprotonated at physiologic pH were more effective in modu lating basal binding (at 100 mu M 1,3-diamine) than analogues which we re mostly diprotonated or unprotonated. Finally, the internuclear dist ance between the amino nitrogens and the extent of modulation of basal [H-3]MK-801 binding were correlated. Similar, but more modest, effect s were seen for spermine-enhanced [H-3]MK-801 binding. These results a re consistent with the existence of two polyamine binding sites associ ated with the NMDA receptor complex. One of the sites appears to prefe rentially recognize lipophilic substances while the other favors hydro philic materials. Both sites appear to recognize polyamines with at le ast one charged (protonated) amino group and one uncharged amino group . The distance between amino groups is a determining factor as well.