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Anthraquinone polyamines: novel channel blockers of N-methyl-d-aspartate receptors

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Summary.

Polyamines, in particular spermine, as well as some natural and synthetic polyamine derivatives have been found to be blockers of N-methyl-d-aspartate receptors. We developed novel, polyamine-based channel blockers to analyze the structure of NMDA receptors. Anthraquinone polyamines block NMDA receptors with some selectivity compared to other glutamate receptors. Results using mutant NR1 and NR2 subunits identified amino acid residues that influence blockade by anthraquinone polyamines. The head group (anthraquinone) may be positioned at the selectivity filter/narrowest constriction of the channel and the polyamine tail penetrates this constriction into the inner vestibule below the level of the selectivity filter. The results are consistent with other work showing that NR1 (Asn616) and NR2B (Asn616), but not NR2B (Asn615), make the narrowest constriction of NMDA channel, and that the M3 segments from the two subunits, which form the outer vestibule, are likely staggered relative to each other in the vertical axis of the channel.

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Abbreviations

AMPA:

α-aminio-3-hydroxy-5-methyl-4-isoxazolepropionic acid

AQP:

anthraquinone polyamine

AQ33:

N 1-(anthraquinone-2-carbonyl)norspermidine

AQ33b:

4-(anthraquinone-2-carbonyl)-4-azaheptane-1,7-diamine

AQ34:

N 1-(anthraquinone-2-carbonyl)spermidine

AQ343:

N 1-(anthraquinone-2-carbonyl)spermine

AQ444:

N 1-(anthraquinone-2-carbonyl)homospermine

MK801:

dizocilpine maleate

NMDA:

N-methyl-d-aspartate

TB34:

N 1,N 4,N 8-tribenzylspermidine

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Authors and Affiliations

  1. Faculty of Pharmacy, Chiba Institute of Science, Choshi, Japan

    K. Kashiwagi

  2. Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York, USA

    K. Williams

  3. Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

    K. Igarashi

Authors
  1. K. Kashiwagi
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  2. K. Williams
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  3. K. Igarashi
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Kashiwagi, K., Williams, K. & Igarashi, K. Anthraquinone polyamines: novel channel blockers of N-methyl-d-aspartate receptors. Amino Acids 33, 299–304 (2007). https://doi.org/10.1007/s00726-007-0520-5

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