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)octanediamine and bis-(3-aminopropyl)nonanediamine (TE393) markedly inhibited [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) binding at equilibrium in the presence of added spermidine (SPD) in "non-washed" rat brain synaptic membranes, without affecting that in the absence of added SPD. Although TE393 significantly potentiated [3H]MK-801 binding before equilibrium in the presence of L-glutamic acid (Glu) alone or both Glu and glycine (Gly) added in "Triton-treated" membranes, the putative polyamine antagonists 1,10-decanediamine (DA10) and arcaine invariably inhibited binding irrespective of the addition of agonists. In the absence of added SPD, in addition, TE393 markedly enhanced abilities of both Glu and Gly to potentiate [3H]MK-801 binding before equilibrium. However, TE393 induced a rightward shift of the concentration-response curve of SPD for [3H]MK-801 binding before equilibrium. Moreover, TE393 was effective in potentiating binding of an antagonist but not an agonist radioligand to the NMDA domain and in inhibiting binding of an antagonist but not an agonist radioligand to the Gly domain. The potentiation of NMDA antagonist binding by TE393 occurred in a manner sensitive to prevention by arcaine but not by DA10. These results suggest that TE393 may be a novel ligand at the polyamine domain with an ability to interact with both the NMDA and Gly recognition domains in antagonist-preferring forms.
Yoneda
Y
Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Ogita
K
K
Enomoto
R
R
Kojima
S
S
Shuto
M
M
Shirahata
A
A
Samejima
K
K
D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D003959:Diamines / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D008297:Male; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism*
D015317:Biogenic Polyamines; D003959:Diamines; D016194:Receptors, N-Methyl-D-Aspartate; C095330:TE 393; D016291:Dizocilpine Maleate