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CELLULAR AND MOLECULAR

Comparative Studies of Anthraquinone- and Anthracene-Tetraamines as Blockers of N-Methyl-D-aspartate Receptors

Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (L.J., H.S., M.T., D.K., K.N., M.K., H.Ta., K.I.); Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Chiba, Japan (H.To., K.K.); Department of Chemistry, University of Central Florida, Orlando, Florida (N.K., O.P.); Faculty of Medical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (T.O.); and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York (K.W.)

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.

Address correspondence to: Dr. Kazuei Igarashi, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. E-mail: iga16077{at}p.chiba-u.ac.jp

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