Epibatidine

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine. Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine. Epibatidine is toxic. Its toxicity stems from its ability to interact with nicotinic and muscarinic acetylcholine receptors. These receptors are involved in the transmission of painful sensations, and in movement, among other functions. Epibatidine then causes numbness, and, eventually, paralysis. Doses are lethal when the paralysis causes respiratory arrest. Originally, it was thought that epibatidine could be useful as a drug. However, because of its unacceptable therapeutic index, it is no longer being researched for potential therapeutic uses. Epibatidine was discovered by John W. Daly in 1974. It was isolated from the skin of Epipdobates anthonyi frogs collected by Daly and colleague, Charles Myers. Between 1974 and 1979, Daly and Myers collected the skins of nearly 3000 frogs from various sites in Ecuador, after finding that a small injection of a preparation from their skin caused analgesic (painkilling) symptoms in mice with symptoms that resembled those of an opioid. Despite its common name - Anthony's Poison Arrow frog - suggesting that it was used by natives when hunting, a paper written by Daly in 2000 claimed that there was no local folklore or folk medicine surrounding the frogs and that they were considered largely unimportant by the locals. The structure of epibatidine was elucidated in 1992, an effort hindered by E. anthonyi gaining IUCN protected status in 1984. Furthermore, these frogs do not produce the toxin when bred and reared in captivity, because they do not synthesize epibatidine themselves. Like other poison dart frogs, they instead obtain it through their diet and then sequester it on their skin. Likely dietary sources are beetles, ants, mites, and flies. Overcoming the difficulties, the structure was eventually determined, and the first synthesis of epibatidine was completed in 1993. Many other synthesis methods have been developed since. Because of its analgesic effect, there was intense interest in epibatidine's use as a drug, because it was found not to be an opioid. This meant that it could potentially be used without fear of addiction. However, it was soon found that it cannot be used in humans because the dose resulting in toxic symptoms is too low for it to be safe. Several total synthesis routes have been devised due to the relative scarcity of epibatidine in nature. After the discovery of the structure of epibatidine, more than fifty ways to synthesize it in the laboratory have been devised. In the first reported example, a nine-step procedure produces the substance as a racemate (in contrast, the naturally occurring compound is the (+)-enantiomer; the (−)-enantiomer does not occur naturally). It was later determined that the (+) and (-) enantiomers had equivalent analgesic as well as toxic effects. The process has proven to be quite productive, with a yield of about 40%. An enantioselective synthesis reported by E J Corey starting from chloronicotinaldehyde is outlined below: In addition to Corey's method, other notable methods include those of Broka, Huang and Shen, and Clayton and Regan.