Abstract
The effects of benzyl-polyamines were studied at recombinantN-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 aKd(0) value of 5 μM and a zδ value of 1.41 at NR1/NR2B channels, whereas the affinity of binding [Kd(0) = 250 μM] but not the degree of voltage-dependence (zδ = 1.43) was much lower at NR1/NR2D channels. At a concentration of 10 μM, TB-3–4 had no effect on α-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.
Footnotes
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Send reprint requests to: Dr. Keith Williams, Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104-6084.
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↵1 This work was supported by United States Public Health Service Grant NS35047 from the National Institute of Neurological Disorders and Stroke, a Grant-in-Aid from the American Heart Association and a grant from the Japan Health Sciences Foundation.
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↵2 Visiting scientists were supported by an International Scientific Research Program from the Ministry of Education, Science, Sports and Culture, Japan.
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↵3 N,N′-Di-benzyl-diamines are referred to by the nomenclature DB-3, DB-7 and so forth, in which the number represents the number of methylene groups separating the amino groups. Thus, N1,N7-di-benzyl-diaminoheptane is DB-7. N,N′-Di-benzyl-triamines are referred to by the nomenclature DB-3–4, DB-4–4 and so forth, in which the numbers represent the number of methylene groups separating the amino and imino groups. Thus, N1,N8-di-benzyl-spermidine is DB-3–4. Similarly, N,N′-di-benzyl-tetra-amines are referred to by the nomenclature DB-3–4–3 and so forth, and N,N′,N′′-tri-benzyl-triamines are referred to by the nomenclature TB-3–4, TB-4–4 and so forth. Thus, N1,N4,N8-tri-benzyl-spermidine is TB-3–4.
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↵4 This work and K. Williams, unpublished observations.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- GluR
- glutamate receptor
- N1-DnsSpm
- N1-dansyl-spermine
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- I-V
- current-voltage
- Received May 14, 1997.
- Accepted July 30, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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Benzyl-polyamines: Novel, PotentN-Methyl-d-aspartate Receptor Antagonists
