SEARCH FOR NOVEL LIGANDS SELECTIVE AT A POLYAMINE RECOGNITION DOMAIN ON THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX USING MEMBRANE-BINDING TECHNIQUES

Among over 60 polyamine derivatives tested, only N-(3-aminopropyl)octa nediamine and bis-(3-aminopropyl)nonanediamine (TE393) markedly inhibi ted 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) bindin g at equilibrium in the presence of added spermidine (SPD) in ''non-wa shed'' rat brain synaptic membranes, without affecting that in the abs ence of added SPD. Although TE393 significantly potentiated [H-3]MK-80 1 binding before equilibrium in the presence of L-glutamic acid (Glu) alone or both Glu and glycine (Gly) added in ''Triton-treated'' membra nes, the putative polyamine antagonists 1,10-decanediamine (DA10) and arcaine invariably inhibited binding irrespective of the addition of a gonists. In the absence of added SPD, in addition, TE393 markedly enha nced abilities of both Glu and Gly to potentiate [H-3]MK-801 binding b efore equilibrium. However, TE393 induced a rightward shift of the con centration-response curve of SPD for [H-3]MK-801 binding before equili brium. Moreover, TE393 was effective in potentiating binding of an ant agonist but not an agonist radioligand to the NMDA domain and in inhib iting binding of an antagonist but not an agonist radioligand to the G ly domain. The potentiation of NMDA antagonist binding by TE393 occurr ed in a manner sensitive to prevention by arcaine but not by DA10. The se results suggest that TE393 may be a novel ligand at the polyamine d omain with an ability to interact with both the NMDA and Gly recogniti on domains in antagonist-preferring forms.