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CELLULAR AND MOLECULAR

Anthraquinone Polyamines: Novel Channel Blockers to Study N-Methyl-D-Aspartate Receptors

Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (K.K., I.T., M.T., H.S., K.I.); Faculty of Medical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (T.O., M.O.); and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York (T.N.S., K.W.)

The effects of various anthraquinone polyamines (AQP) were studied at recombinant N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus laevis oocytes. The AQP derivatives had different numbers of methylene groups between the NH₂ (or NH) groups in their spermidine-like tail. Thus, we termed these derivatives AQ33, AQ34, etc. All AQP derivatives inhibited responses of NR1/NR2 receptors in oocytes voltageclamped at -70 mV, with IC₅₀ values between 4 and 22 µM. The block was strongly voltage-dependent. AQ34 and AQ33b inhibited responses of NR1/NR2 receptors but did not inhibit responses of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors expressed from GluR1 or GluR2(Q), indicating that AQ34 and AQ33b are preferential NMDA antagonists. Results of experiments using mutant NR1 and NR2 subunits identified residues that influence block by AQ34 and AQ33b. These residues are located in the outer vestibule at the selectivity filter/narrowest constriction of the channel and in the inner vestibule below the level of the selectivity filter. The results with mutant NR1 and NR2 subunits are consistent with the idea that NR1(Asn616) and NR2B(Asn616), but not NR2B(Asn615), make the narrowest constriction of NMDA channel.

Address correspondence to: Dr. Kazuei Igarashi, Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. E-mail: iga16077{at}p.chiba-u.ac.jp

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