Abstract
Anthraquinone spermine [N1-(anthraquinone-2-carbonyl)spermine; AQ343], anthraquinone homospermine [N1-(anthraquinone-2-carbonyl; AQ444], anthracene spermine [N1-(9-anthracenylmethyl)spermine; Ant343], and anthracene homospermine [N1-(9-anthracenylmethyl)homospermine; Ant444] were found to be potent antagonists of recombinant N-methyl-d-aspartate (NMDA) receptors (NRs). The effects of both anthraquinone (AQ)- and anthracene (Ant)-tetraamines were reversible and voltage-dependent. Results of experiments using mutant NR1 and NR2B subunits of NMDA receptor identified residues that influence block by AQ- and Ant-tetraamines. The results indicate that the polyamine tail is crucial for block by AQ- and Ant-tetraamines. Residues in the outer vestibule of the NR1 subunit were more strongly involved in block by AQ-and Ant-tetraamines than residues in the corresponding region of NR2B. Several amino acid residues in the inner vestibule, below the level of the selectivity filter of NR1 and NR2B, affected block by AQ444, Ant343, and Ant444, but they did not affect block by AQ343. AQ-tetraamines could permeate the channel at very negative membrane potentials when the narrowest constriction of the channel was expanded by replacing the Asn residue at Asn616 of NR1 and NR2B with Gly, whereas Ant-tetraamines did not easily pass through the channel, apparently because of differences in the relative position of the head groups on AQ- and Ant-polyamines.
Footnotes
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This work was supported by the National Institutes of Health Grant NS-35047; a grant-in-aid for scientific research from the Ministry of Education, Culture, Science and Technology, Japan; the Sankyo Foundation of Life Science, Japan; and the Tokyo Biochemical Research Foundation, Japan. L.J. and H.S. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.110528.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; NR, N-methyl-d-aspartate receptor; GluR, glutamate receptor; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; AQ34, N′-(anthraquinone-2-carbonyl)spermidine; AQ33b, 4-(anthraquinone-2-carbonyl)-4-azaheptane-1,7-diamine; AQ343, N1-(anthraquinone-2-carbonyl)spermine; AQ444, N1-(anthraquinone-2-carbonyl)homospermine; Ant343, N1-(9-anthracenylmethyl)spermine; Ant444, N1-(9-anthracenylmethyl)homospermine; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MD, molecular dynamics; AQ, anthraquinone-2-carboxyl group; Ant, 9-anthracenylmethyl group; AMPA, α-aminio-3-hydroxy-5-methyl-4-isoxazolepropionic acid; I-V, current-voltage.
- Received July 8, 2006.
- Accepted October 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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