Modulation by both diphenyliodonium and diphenyleneiodonium of [3H]MK-801 binding to rat brain synaptic membranes

Binding of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) was significantly inhibited by the addition of several different compounds related to generation of nitric oxide (NO) at 100 microM in rat brain synaptic membranes. These included sodium nitroprusside, diphenyliodonium (DI), diphenyleneiodonium (DPI) and methylene blue. However, neither S-nitroso-N-acetylpenicillamine nor S-nitroso-L-glutathione inhibited binding at 100 microM. Both DI and DPI inhibited binding in a concentration-dependent manner at a concentration range of over 1 microM, while further addition of spermidine (SPD) significantly attenuated the potency of DPI to inhibit binding without affecting that of DI. In contrast, SPD induced significant potentiation of the ability of unlabelled MK-801 to displace [3H]MK-801 binding in a fashion sensitive to antagonism by the novel polyamine antagonist bis-(3-aminopropyl)nonanediamine. This novel polyamine antagonist also prevented the reversing effect of SPD on inhibition by DPI of [3H]MK-801 binding. Moreover, DPI competitively exacerbated the ability of SPD to potentiate [3H]MK-801 binding in the presence of both L-glutamic acid and glycine at maximally effective concentrations. On the other hand, SPD was effective in reversing the inhibition by DPI in cerebellar, but not hippocampal, synaptic membranes. These results suggest that both DI and DPI may modulate synaptic responses mediated by the N-methyl-D-aspartate receptor through inhibition of opening processes of the ion channel in a manner irrespective of generation of NO radicals in particular situations. Possible involvement of the polyamine domain in the inhibition by DPI is also suggested.