Natural products provide a wide range of biologically active agents,many of which have unique profiles of pharmacological activity and therapeutic potential. Over five 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/allopumiliotoxins and related homopumiliotoxins, 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 and 5,8-disubstituted indolizidines, 1,4-disubstituted and 4,6-disubstituted quinolizidines, an unique class of 3,5-disubstituted homoindolizidines (azabicyclo[5.3.0]decanes), and a variety of tricyclic alkaloids, including pyrrolizidine oximes,gephyrotoxins, pseudophrynamines, cyclopentaquinolizidines and coccinellines. Many of these are noncompetitive blockers of nicotinic receptor channels; some are selective and others nonselective. Most of the five hundred alkaloids have been detected and characterized from skin of neotropical dendrobatid frogs. Lipophilic alkaloids also occur in skins from one genus of Australian myobatrachid frogs, one genus of South American bufonid toads and 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, representing a total of eight structural classes. The origin of the batrachotoxins, histrionicotoxins, pumiliotoxins, epibatidines and the remaining dozen other structural classes found in frog skin remains a mystery. Histrionicotoxins and the homoindolizidines will probably be of ant origin. 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 batrachotoxins is unknown. A unusual alkaloid present in muscle, which appears to protect such birds from the highly toxic homobatrachotoxin, has been characterized but a tentative structure must be confirmed by synthesis. Structures have now been determined for a 4,6-disubstituted quinolizidine, an unusual 5,6,8- trisubstituted indolizidine containing a branched side chain, an oxirane-containing allopumiliotoxin and a homoindolizidine. A peptide in skin extracts from a hylid frog that inhibits the binding of glibenclamide to ATP-dependent potassium channels is has been defined, but it now appears that PLA(2) activity of the peptide (mw 4737) confers activity. A CI/MS collision activated mass spectrometric technique has been developed and is being used to obtain and intepret fragmentations entirely different than the radical fragmentations obtained from EI spectra. The data has already defined one new alkaloid class and provide definitive evidence for another.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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