title: Biological activity of 8,11-dideoxytetrodotoxin: lethality to mice and the inhibitory activity to cytotoxicity of ouabain and veratridine in mouse neuroblastoma cells, Neuro-2a.
abstract: Contribution of the C-8 hydroxyl group of tetrodotoxin to its sodium channel blocking activity has never been clearly evaluated. Isobe et al. recently synthesized 8,11-dideoxytetrodotoxin, the first 8-deoxy analog of tetrodotoxin. In this study, the biological activity of this compound was investigated to compare with that of 11-deoxytetrodotoxin. Intraperitoneal injection of 8,11-dideoxytetrodotoxin at the level of 700 microg/kg did not kill a mouse (n=2), indicating that the lethal dose of this compound was more than 70 and 10 folds larger than LD(50) of tetrodotoxin and 11-deoxytetrodotoxin, respectively. The inhibitory activity of 8,11-dideoxytetrodotoxin to cytotoxicity of ouabain and veratridine in mouse neuroblastoma cells (Neuro-2a) was also examined. The ED(50) for 8,11-dideoxytetrodotoxin was estimated to be 9.3+/-3.3 microM (n=3), approximately 2000 and 34 folds larger than those of tetrodotoxin (4.6+/-0.70 nM, n=3) and 11-deoxytetrodotoxin (270+/-74 nM, n=4), respectively. These data suggest that the C-8 hydroxyl group of tetrodotoxin is also important for its activity, as well as all the other hydroxyl groups.
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba, Sendai 981-8555, Japan. myama@biochem.tohoku.ac.jp
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.forename: Masanori
authors.initials: M
authors.lastname: Asai
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009447:Neuroblastoma / Q000378:metabolism*; D010042:Ouabain / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000031:analogs & derivatives* / Q000633:toxicity*; D014701:Veratridine / Q000633:toxicity*
chemical_list: C465250:8,11-dideoxytetrodotoxin; D004791:Enzyme Inhibitors; C064101:11-deoxytetrodotoxin; D013779:Tetrodotoxin; D010042:Ouabain; D014701:Veratridine