Batrachotoxin pyrrole-3-carboxylate

Physical and spectral properties of batrachotoxins are presented in Table I. Mass spectra have been presented and interpreted (3,13,14). The parent ion of batrachotoxin is virtually nondetectable by direct probe methods, and instead an apparent molecular ion of miz 399 is seen, probably because of pyrolytic elimination of the pyrrole carboxylate moiety. Batrachotoxin alkaloids do not chromatograph on capillary gas chromatographic columns, but a pyrolysis product has been detected at 280°C on the temperature-programmed, packed OV-1 columns used for analysis of other dendrobatid alkaloids (see Appendix). The pyrrole carboxylate moiety is responsible for major ions of C7H9N02 (m/z 139), C6H9N ... 

The most famous of the many alkaloids isolated so far is without any doubt batrachotoxin and its derivatives. Batrachotoxin has a LD50 of 2 ug per kg body weight (mouse, i.m.), thus being the most toxic nonprotein substance at all. Because of its special pharmacologic activity to keep open irreversably the sodium channels of nerve cells it has become an important tool in the studies of sodium channels. Chemically the batrachotoxins are esters of a 20-hydroxy steroid, batrachotoxinin A, with different pyrrol carboxylic acids. Although the activities of the different batrachotoxins is qualitatively the same, it differs quantitatively according to the acid part of the molecule (refs. 14, 15). 

The mass spectra of batrachotoxin and homobatrachotoxin could now be readily interpreted. Indeed, it even proved possible to detect the molecular ion at 538 for batrachotoxin, but its intensity even under the most favorable conditions was only about two percent of the apparent molecular ion at 399. Furthermore, the true molecular ion at 538 could never be observed except transiently probably due to pyrolytic elimination of the pyrrole carboxylate moiety. The pyrrole carboxylate moiety was responsible for major ions of C7H9NO2 (m/z 139) and QHgN, QHgN (m/z 95,94) in batrachotoxin and for major ions of CgH]]N02 (m/z 153), C7H8NO2, C7H11N (m/z 109) and CgHgN in homobatrachotoxin (see Table 1 at the end of this section). 

Structure activity correlations for analogs of batrachotoxin have been studied to a limited extent. Toxicity in white mice (Table 4 at the end of this section) (251), effects on nerve-striated muscle preparations (268), cardiac preparations (233), ATPase (79), and eel electroplax (cited in 5) show similar profiles with the different analogs. The substitution pattern on the pyrrole moiety is important. The relative order of activity of certain substituted pyrrole carboxylates in a neuromuscular preparation as depolarizing agents was as follows Batrachotoxin > homobatrachotoxin =... 

Phyllobates aurotaenia inhabits South America, where it is known as kokoi. A toxic material is secreted from the skin, and the secretion is utilized as an arrow poison. The toxic material was studied at the National Institutes of Health (U.S.A.), and batrachotoxin was reported as the main toxic component in 1969 [1]. Although there are no reports on the biosynthesis of this compound, it appears that in this alkaloid the nitrogen atom was incorporated into a steroid skeleton. A nitrogen atom has also been introduced into the side-chain moiety in the form of a pyrrole-3-carboxylic acid derivative. The LD50 value of batrachotoxin is 2 xg/kg (mouse/subcutaneous injection). 

The unique pyrrole-3-carboxylate moiety of batrachotoxin has not proven to be essential to high activity in these alkaloids since the corresponding benzoate is very active (46). 2,4,5-Trimethylpyrrole carbo-xylates of codeine, ephedrine, jervine, scopoline and methylreserpate have been prepared using trifluoroacetic in a mixed anhydride procedure (272). The scopoline derivative showed modest analgesic activity. 

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