Two hundred pharmacologically active alkaloids have been identified in extracts of frog skins. Such alkaloids serve the frogs in chemical defense against predators. New structural classes of amphibian alkaloids include 2,5-disubstituted pyrrolidines, 2,6-disubstituted piperidines, a 7-alkylidene-9-hydroxy-9-methylquinolizide, 3-substituted-8-methylindolizidines, 2,5-disubstituted decahydroquinolines and amidines. The alkaloids exhibit a range of pharmacological activities. The steroidal batrachotoxins are potent activators of voltage-dependent sodium-channels. Antagonism of binding of a radioactive batrachotoxin analog to a site on sodium channel provides a rapid assay for local anesthetic activity in a wide range of compounds. Local anesthetics compete for binding through an indirect allosteric mechanism, thereby enhancing off rates, while certain alkaloids and diterpenes compete directly for the binding site. The spiropiperidine histrionicotoxins block the nicotinic acetylcholine receptor-channel complex and voltage-dependent sodium and potassium channels. Histrionicotoxins increase the affinity of nicotinic agonists for the receptor, apparently by allosterically enhancing desensitization of the receptor channel complex. The binding of a radioactive analog of histrionicotoxin to a site on the acetylcholine receptor channel is enhanced by nicotinic agonists and is antagonized by a variety of drugs including other frog alkaloids, local anesthetics, and phencyclidine. Pumiliotoxin B, an alkylidene-hydroxyindolizidine, augments direct and indirect-evoked muscle contraction in neuromuscular preparations. Pumiliotoxin B and certain congeners also have potent positive chronotropic and inotropic effects in heart. The mechanism of action of the pumiliotoxins appears unique and appears to facilitate evoked release of calcium ions from internal storage sites in nerve and muscle through activation of phosphatidylinositol turnover.
