Natural products provide a wide range of biologically active agents, many of which have unique profiles of pharmacological activity and therapeutic potential. Over four hundred alkaloids have been identified in extracts from amphibian skins. These include batrachotoxins, which are potent activators of sodium channels, histrionicotoxins, which are noncompetitive blockers of nicotinic receptor-channels and potassium channels, pumiliotoxins, which have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, an extremely potent and selective nicotinic agonist with remarkable antinociceptive activity. Further alkaloids include 2,5-disubstituted decahydroquinolines, 3,5-disubstituted pyrrolizidines , 3,5-disubstituted indolizidines, 5,8-disubstituted indolizidines, 1,4-disubstituted and 4,6-disubstituted quinolizidines, the pumiliotoxin-homopumiliotoxin-allopumiliotoxin class, and a variety of tricyclic alkaloids, including pyrrolizidine oximes, gephyrotoxins, seudophrynamines, cyclopentaquinolizidines and coccinellines. Many of these are noncompetitive blockers of nicotinic receptor channels; some are selective and others nonselective. Most of the four hundred alkaloids have been detected and characterized from skin of neotropical dendrobatid frogs. Pumiliotoxins also occur in one genus of Australian myobatrachid frogs, in one genus of South American bufonid toads and in one genus of Madagascan mantellid frogs. It appears all frog skin alkaloids have a dietary origin, being taken up and sequestered unchanged into skin glands. The uptake system appears conserved for the four family groups that contain skin alkaloids, at least with respect to alkaloid substrates. Ants, beetles and millipedes appear to be the source of certain frog skin alkaloids. Decahydroquinolines and 4,6-disubstituted quinolizidines have now been discovered in ants. The origin of the batrachotoxins, histrionicotoxins, pumiliotoxins, and epibatidines found in frog skin remains a mystery. Homobatrachotoxin is present in feathers and skin of some, but not all populations of several species of passerine birds of the genus Pitohui that occur in Papua New Guinea. Whether the birds also are dependent on a dietary source for homobatrachotoxin is unknown. A unusual alkaloid present in muscle, which appears to protect such birds from the highly toxic homobatrachotoxin, is being characterized. Structures have now been determined for a 4,6-disubstituted quinolizidine, an unusual trisubstituted indolizidine. Containing a branched side chain, an oxirane-containing allopumiliotoxin and a unprecedented disubstituted decahydropyrroloazepine. A series of tropane alkaloids related to the chinese herbal alkaloid baogongteng-A and further methylisooxazole analogs of the potent nicotinic analgetic epibatidine have been synthesized for biological evaluation as nicotinic and muscarinic agonists. A peptide in skin extracts from a hylid frog that inhibits the binding of glibenclamide to ATP-dependent potassium channels is being isolated.
NIH ExPorter
NIH ExPorter