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Research ArticleArticle

Effects of Specific Modifications of Several Hydroxyls of Tetrodotoxin on Its Affinity to Rat Brain Membrane

Mari Yotsu-Yamashita, Atsuko Sugimoto, Akira Takai and Takeshi Yasumoto
Journal of Pharmacology and Experimental Therapeutics June 1999, 289 (3) 1688-1696;
Mari Yotsu-Yamashita
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Atsuko Sugimoto
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Akira Takai
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Takeshi Yasumoto
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Abstract

The widely used sodium channel blocker tetrodotoxin (TTX) is a compound that has six hydroxyl residues at the C-4, C-6, C-8, C-9, C-10, and C-11 positions in addition to a guanidinium group, which is positively charged in biological pH range. Thirteen analogs of this toxin with structural modifications involving one or more of these hydroxyls were examined on their affinity to a rat brain membrane preparation, which is known to contain sodium channels abundantly. The equilibrium dissociation constants associated with the binding of TTX and its analogs to the sodium channels were estimated, from their ability to inhibit the binding of [3H]saxitoxin, as follows (in nM): TTX, 1.8; chiriquitoxin, 1.0; 11-oxoTTX, 1.5; 11-norTTX-6,6-diol, 1.6; 11-norTTX-6(S)-ol, 23; 11-norTTX-6(R)-ol, 31; 11-deoxyTTX, 37; 6-epiTTX, 39; 4-epiTTX, 68; 4,9-anhydroTTX, 180; TTX-8-O-hemisuccinate, >380; TTX-11-carboxylic acid, >2300; tetrodonic acid, >3600; 5,6,11-trideoxyTTX, >5000. The reduction of the affinity observed with the analogs involving reduction or translocation of the hydroxyls at C-6 and C-11 is indicative of the contribution of these residues to the binding to sodium channels as hydrogen bond donors. The especially large value of the dissociation constant for TTX-11-carboxylic acid is consistent with the idea that the C-11-hydroxyl forms a hydrogen bond with a carboxylic acid residue of the channel protein. The markedly low affinity of TTX-8-O-hemisuccinate may possibly be ascribable to intramolecular salt-bridge formation, which neutralizes the positive charge of the guanidinium group.

Footnotes

  • Send reprint requests to: Mari Yotsu-Yamashita, Graduate School of Agriculture, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan. E-mail:myama{at}biochem.tohoku.ac.jp

  • ↵1 This work was supported by Grants-in-Aid 07102002 and 10760043 from the Ministry of Education, Science, Sports and Culture of Japan, a Suntory Institute for Bioorganic Research grant, and grants from the Naito Foundation and the Hayashi Memorial Foundation for Female Natural Scientists. A.T. is a member of a Research for the Future Program of the Japan Society for the Promotion of Science (project number: 96L00504).

  • ↵2 Present address: Japan Food Research Laboratories, 6-11-10 Nagayama, Tama-shi, Tokyo 206-0025, Japan.

  • Abbreviations:
    TTX
    tetrodotoxin
    STX
    saxitoxin
    FAB-MS
    fast atom bombardment-mass spectroscopy
    • Received December 9, 1998.
    • Accepted February 16, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 3
1 Jun 1999
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Research ArticleArticle

Effects of Specific Modifications of Several Hydroxyls of Tetrodotoxin on Its Affinity to Rat Brain Membrane

Mari Yotsu-Yamashita, Atsuko Sugimoto, Akira Takai and Takeshi Yasumoto
Journal of Pharmacology and Experimental Therapeutics June 1, 1999, 289 (3) 1688-1696;

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Research ArticleArticle

Effects of Specific Modifications of Several Hydroxyls of Tetrodotoxin on Its Affinity to Rat Brain Membrane

Mari Yotsu-Yamashita, Atsuko Sugimoto, Akira Takai and Takeshi Yasumoto
Journal of Pharmacology and Experimental Therapeutics June 1, 1999, 289 (3) 1688-1696;
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