Alkaloids from frog skins: selective probes for ion channels and nicotinic receptors

Amphibian skin has provided a wide range of biologically active alkaloids, many of which have unique profiles of pharmacological activity and therapeutic potential. Over three hundred alkaloids have been identified and structures of over a dozen different classes of alkaloids have been elucidated. These include the batrachotoxins, which were shown to be potent and selective activators and ligands for sodium channels, the histrionicotoxins, which were shown to be potent non-competitive blockers and ligands for nicotine receptor channel complexes, the pumiliotoxins and related allo- and homo-pumiliotoxins, which were shown to have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, which was shown to have potent antinociceptive activity due to selective agonist activity at nicotinic receptors. These alkaloids are known in nature only in amphibian skin, except for homobatrachotoxin, which was recently identified in feathers and skin of a bird. Further classes of alkaloids from amphibian skin include monocyclic pyrrolidines and piperidines, bicyclic decahydroquinolines, pyrrolizidines, indolizidines, and quinolizidines and tricyclic gephyrotoxins, pyrrolizidine oximes, pseudophrynamines, and coccinellines. These alkaloids also have activity in ion channels. It appears likely that all of the frog skin alkaloids are taken up and sequestered into the skin from the diet, which for such amphibians consists mainly of small arthropods. The pyrrolidines, piperidines, 3,5-disubstituted pyrrolizidines and 3,5-disubstituted indolizidines appear likely to be derived from ants, the coccinellines and related tricyclics from beetles and the pyrrolizidine oximes from millipedes. The origins of the batrachotoxins, histrionicotoxins, pumiliotoxins and epibatidine are of particular interest in view of their remarkable biological activities.