Batrachotoxinins

Brown GB, Gaupp JE, Olsen RW (1988) Pyrethroid insecticides stereospecific allosteric interaction with the batrachotoxinin-a benzoate binding site of mammalian voltage-sensitive sodium channels. Mol Pharmacol 34 54-59... 

Friese J, Gleitz J. (1998). Kavain, dihydrokavain, and dihydromethysticin non-competitively inhibit the specific binding of [3FI]-batrachotoxinin-A 20-alpha-... 

A/steroid 2000A Daly 2000 H batrachotoxinin A Dendrobatidae fi-ogs/lab tool for the study of Na channels... 

Pauwels, P.J., Leysen, J.E., Laduron, P.M. pH] Batrachotoxinin A20-a-benzoate binding to sodium channels in rat brain characterization and pharmacological significance, Eur. J. Pharmacol. 1986, 124, 291-298. 

Unique structural features of this steroidal alkaloid are the cis junctions between rings A/B and C/D, the ether linkage between C-3 and C-9, the OH group on C-11, and the alkaloid function in a seven-membered ring formed by a methylethylamine moiety bridging the methyl on C-13 and OH on C-14 of a steroid nucleus. A reanalysis of the spectral data showed that batrachotoxin is the 20-a-dimethylpyrrole carboxylate and homobatrachotoxin the 20-a-ethylmethylpyrrolc carboxylate of batrachotoxinin A (31). 

Fig. 9. Sections from a three-dimensional electron-density map for the O-p-bromobenzoate derivative of batrachotoxinin A (2). The contours are spaced by 2e/A3.

The formation of dioxolane derivatives from a, p-unsaturated carbonyls is often accompanied by migration of the double bond and the extent of migration depends on the strength of the acid catalyst and the reaction conditions As can be seen from Scheme 2.32, weaker adds (pKa > 3) leave the double bond intact whereas stronger acids cause partial or complete isomerisation,70 The isomerisation of the double bond is not necessarily a disaster indeed, in some cases it can be a useful synthetic tool. For example. Kishi exploited the isomerisation in a concise synthesis of Batrachotoxinin A,71 the initial steps of which are shown in Scheme 2.33. and there are many other examples of a similar nature.72-76... 

Batrachotoxin, not unexpectedly in view of its use as a dart poison by South American Indians, is an extremely toxic substance. The LDjq on subcutaneous injection in mice is about 40 ng. Homobatrachotoxin is only slightly less toxic, while batrachotoxinin A is 500-fold less toxic. The nature of the ester function at the 20a position is of critical importance to toxicity. Thus, the 20a-benzoate of batrachotoxinin A is fully as toxic as batrachotoxin, whereas the 20a-4-bromobenzoate has very low toxicity. For a summary of the toxicides of natural and synthetic batrachotoxins, see Ref. 5. 

Batrachotoxin at present remains an important, indeed often essential, tool for mechanistic studies of the function of voltage-dependent sodium channels and for the investigation of the role of depolarization and/or influx of sodium ions on physiological functions. Batrachotoxin has been particularly useful in the study of the function of sodium channels, purified and reconstituted into artificial lipid bilayers. A summary and overview of the extensive studies with batrachotoxin appeared in 1986 (5). Since that time more than 100 articles dealing with the activity of batrachotoxin and/ or the radioligand batrachotoxinin A 20a-[ H]benzoate have appeared, and it is beyond the scope of the present review to summarize this extensive recent literature. A few selected developments are as follows allosteric enhancement of the action of batrachotoxins by pyrethroid insecticides... 

A different approach (Scheme 39) to the synthesis of the 14,18-oxyethano-iV-methylimino-bridge of batrachotoxinin used the epoxy-pregnane (473) as starting material. This was converted by conventional techniques into the keto-lactone (474). Bromination and dehydrobromination of (474) gave the A -16-ketone, which was reduced to the allylic alcohol and epoxidized to (475). Hydride... 

The deoxygenation of the C6 position of an advanced intermediate was accomplished in a two-step procedure by Y. Kishi et al. in their synthesis of (+)-batrachotoxinin A. " The Luche reduction was followed by the formation of the C6 pyridylthioether, which was desulfurized using Raney nickel. 

A unique class of steroidal alkaloids, the batrachotoxinins, is isolated in small quantities from the skins of poison arrow frogs and also from the feather of a New Guinea bird. One of the key steps during the total synthesis of (+)-batrachotoxinin A by Y. Kishi et al. was a Michael addition to form a seven-membered oxazapane ring. The removal of the primary TBS protecting group was achieved by treatment with TASF and the resulting alkoxide attacked the enone at the 3-position to afford an enolate as the Michael adduct. The enolate was trapped with phenyl triflimide as the end triflate. 

Representative Chemicals Batrachotoxin Ho-mobatrachotoxin Batrachotoxinin A and several other batrachotoxinin A congeners Chemical Abstracts Service Registry Number CAS 23509-16-2 (Batrachotoxin)... 

Synonyms Fhyllobates toxin Pitohui toxin Ifrita toxin poison dart frog toxin Chemical/Pharmaceutical/Other Class Steroidal alkaloid neurotoxin Chemical Formulas o Batrachotoxin C31H42N2O6 o Homobatrachotoxin C32H44N2O6 o Batrachotoxinin-A C24H35NO5... 

Catterall WA, Morrow CS, Daly JW, and Brown GB (1981) Binding of batrachotoxinin A 20-a-benzoate to a receptor site associated with sodium channels in synaptic nerve ending particles. Journal of Biological Chemistry 256 8922-8927. 

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