Summary
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1.
In voltage-clamp experiments on frog myelinated nerve fibers, the effects of nine synthetic derivatives of batrachotoxin (BTX) obtained from 7,8-dihydrobatrachotoxinin A (DBTX-A) on Na+ currents (I Na) have been investigated.
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2.
Both of 20α-esters of DBTX-A with 2,4,5-trimethylpyrrol-3-carboxylic acid (DBTX-P) and benzoic acid (DBTX) at a 10−5 M concentration caused modification ofI Na qualitatively similar to that induced by BTX.
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3.
The quaternary derivative of DBTX (QDBTX) produced such changes inI Na only at a 5 ⋅ 10−4 M concentration, apparently due to its much lower lipid solubility.
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4.
Replacement of a —CH2— by a —C=O· group in the homomorpholine ring near the tertiary nitrogen atom abolished the DBTX activity, strongly suggesting the necessity of tertiary nitrogen protonation for the toxin interaction with the channel receptor.
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5.
Transfer of an 11-hydroxygroup from theα- to theβ-position in the DBTX molecule did not decrease its activity in spite of the fact that in theβ-position this group is sterically very hindered. The activity of 11β-DBTX is at variance with the prediction of Codding's (1983) “oxygen triad” hypothesis.
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6.
DBTX-A and compounds obtained from DBTX by oxidation of the 11α-hydroxygroup (K-DBTX), acetylation (Ac-DBTX), or reduction of the hemiketal moiety (H2DBTX) even at a concentration as high as 10−3 M were able to modify only a very small fraction of the Na channels. However, a clear-cut reversible blocking action on both normal and modified Na channels was observed.
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7.
These results led us to conclude that BTX modifies the Na channels only in the charged form and hemiketal and 20α-ester moieties provide adequate disposition of toxin on the receptor surface. The inability of H2DBTX, DBTX-A, and K-DBTX and Ac-DBTX to modify most of the Na channels can be explained by a low “probability of correct disposition” of these ligands on the receptor surface.
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Khodorov, B.I., Yelin, E.A., Zaborovskaya, L.D. et al. Comparative analysis of the effects of synthetic derivatives of batrachotoxin on sodium currents in frog node of Ranvier. Cell Mol Neurobiol 12, 59–81 (1992). https://doi.org/10.1007/BF00711639
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DOI: https://doi.org/10.1007/BF00711639