TY - JOUR
T1 - Biological activity of 8,11-dideoxytetrodotoxin
T2 - Lethality to mice and the inhibitory activity to cytotoxicity of ouabain and veratridine in mouse neuroblastoma cells, Neuro-2a
AU - Yotsu-Yamashita, Mari
AU - Urabe, Daisuke
AU - Asai, Masanori
AU - Nishikawa, Toshio
AU - Isobe, Minoru
N1 - Funding Information:
This work was supported by a Grants-in Aid from JSPS (No. 14560080, M.Y.Y), and a Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, PRESTO of JST, the Naito Foundation, the Pfizer's Award in Synthetic Organic Chemistry (T.N and M.I), and Mitsubishi Chemical Corporation Fund (TN and MI).
PY - 2003/10
Y1 - 2003/10
N2 - 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 μg/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 LD50 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 ED50 for 8,11-dideoxytetrodotoxin was estimated to be 9.3±3.3 μM (n=3), approximately 2000 and 34 folds larger than those of tetrodotoxin (4.6±0.70nM, n=3) and 11-deoxytetrodotoxin (270±74nM, 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.
AB - 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 μg/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 LD50 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 ED50 for 8,11-dideoxytetrodotoxin was estimated to be 9.3±3.3 μM (n=3), approximately 2000 and 34 folds larger than those of tetrodotoxin (4.6±0.70nM, n=3) and 11-deoxytetrodotoxin (270±74nM, 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.
KW - Ligand-receptor interaction
KW - Sodium channel
KW - Structure-activity relationship
KW - Tetrodotoxin
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U2 - 10.1016/j.toxicon.2003.08.002
DO - 10.1016/j.toxicon.2003.08.002
M3 - Article
C2 - 14529738
AN - SCOPUS:0842326232
VL - 42
SP - 557
EP - 560
JO - Toxicon
JF - Toxicon
SN - 0041-0101
IS - 5
ER -