International Union of Pure and Applied Chemistry

Biodiversity of alkaloids in amphibian skin: A dietary arthropod source*

John W. Daly

Laboratory of Bioorganic Chemistry, NIH, Bethesda, MD 20892-0820, USA
E-mail: [email protected]

Abstract: Amphibian skin has provided a wide range of biologically active alkaloids, many of which have unique profiles of pharmacological activity. Over four hundred alkaloids have been detected and structures of twenty different classes of alkaloids have been elucidated, using gas chromatographic mass spectral and infrared spectral analysis, and after isolation, nuclear magnetic resonance spectroscopy and x-ray crystallography. These include the batrachotoxins, which are potent and selective activators of sodium channels, the histrionicotoxins, which are potent noncompetitive blockers of nicotinic receptor-gated channels, the pumiliotoxins and related allo- and homo-pumiliotoxins, which have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, which has potent antinociceptive activity due to agonist activity at nicotinic receptors. These alkaloids are known in nature only in amphibian skin except for homobatrachotoxin, which was recently identified from a bird. Further classes of alkaloids from amphibian skin include pyrrolidines and piperidines, decahydroquinolines, pyrrolizidines, various indolizidines and quinolizidines and tricyclic gephyrotoxins, pyrrolizidine oximes, pseudophrynamines, coccinellines and cyclopentaquinolizidines. The alkaloids of amphibian skin were originally thought, in view of their uniqueness and often apparent phyllogenetic distribution, to be synthesized by the amphibians, but it is now realized that most if not all are merely accumulated unchanged from dietary sources. The pyrrolidines, piperidines, decahydroquinolines, pyrrolizidines, indolizidines, and quinolizidines appear likely to be derived from ants, the coccinellines from beetles, and the pyrrolizidine oximes from millipedes. The origins of the batrachotoxins, histrionicotoxins, pumillotoxins and epibatidine are of particular interest in view of their remarkable biological activities. Discovery of arthropod sources of alkaloids found in amphibian skin may provide a treasure-trove of further alkaloids. Many other genera of amphibians remain to be investigated for alkaloids and other biologically active substances.

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