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Vol. 283, Issue 2, 533-540, 1997

Benzyl-polyamines: Novel, Potent N-Methyl-D-aspartate Receptor Antagonists1

Kazuei Igarashi2 , Akira Shirahata, Albert J. Pahk, Keiko Kashiwagi2 and Keith Williams

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (K.I., A.J.P., K.K., K.W.), Faculty of Pharmaceutical Sciences, Chiba University, Inage-ku, Chiba 263, Japan (K.I., K.K.), and Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-02, Japan (A.S.)

The effects of benzyl-polyamines were studied at recombinant N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus laevis oocytes. A number of mono-, di- and tri-benzyl polyamines, having benzyl substitutions on the terminal or central amino groups, inhibited responses of NR1/NR2 receptors in oocytes voltage-clamped at -70 mV. Among the most potent compounds was N1,N4,N8-tri-benzyl-spermidine (TB-3-4), which had an IC50 value of 0.2 µM. TB-3-4 was ~40-fold more potent at NR1/NR2A and NR1/NR2B receptors than at NR1/NR2C or NR1/NR2D receptors. Block by TB-3-4 was strongly voltage dependent. Using voltage ramps analyzed by the Woodhull model of voltage-dependent channel block, TB-3-4 was found to have a Kd(0) value of 5 µM and a zdelta value of 1.41 at NR1/NR2B channels, whereas the affinity of binding [Kd(0) = 250 µM] but not the degree of voltage-dependence (zdelta  = 1.43) was much lower at NR1/NR2D channels. At a concentration of 10 µM, TB-3-4 had no effect on alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors expressed from the GluR1 subunit, indicating that TB-3-4 is a selective NMDA antagonist. TB-3-4 did not permeate wild-type NMDA channels but could easily permeate channels containing an N616G mutation in the NR1 subunit. This mutation is presumed to increase the size of the narrowest constriction of the NMDA channel, thus allowing passage of TB-3-4. Benzyl-polyamines such as TB-3-4 represent a structurally novel class of NMDA receptor channel blockers.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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