December 2004

Epipedobates tricolor
[Photo courtesy of Jan Verkade]

For centuries, natives of the Colombian tropical rainforest have prepared for hunting by rubbing the tips of their blow darts on the skin of a tiny frog, aptly nicknamed the "poison-dart" frog. They do this to coat their blow dart tips with a toxin that, even in small amounts, can paralyze or kill animals. In fact, the amount of toxin in just one of these frogs should be enough to kill a huge water buffalo, hundreds of times its size!  

"Toxin" Misuse
The term "toxin" is defined as a poisonous substance that is produced by living organisms. Toxins, therefore, by definition, are natural. "Toxin" is misused when it is used to refer to substances created by industry.

Intrigued by the properties of the toxins from the poison-dart frog, a team led by Dr. John Daly of the U.S. National Institutes of Health tried to analyze the toxins found in the skin of another frog--this one in Ecuador--that scientists call Epipedobates tricolor. Back at the lab, they found that one of the 80 or so toxins in the frog skin caused an interesting reaction in mice--they arched their tails in a way that is characteristic of the effects of certain pain-killers. Amazingly, the scientists determined that the active substance they named "epibatidine" (pronounced: epee-BAT-i-dean) was 200 times more powerful than the best known product we have for pain relief!

Unfortunately, the team found that the amount of epibatidine they had isolated from Epipedobates tricolor--less than one milligram (less than 0.001 gram or 0.0000022 pound)--was not enough to analyze completely. And because the frogs were then declared endangered, the scientists could not obtain any more frogs. So, a small sample of the rare and precious pain-killer was frozen for safekeeping in their laboratory. It wasn't until about a decade later that methods became available that could be used to chemically analyze such small quantities. The good news is that Dr. Daly's determination to understand the frog toxin may one day result in relief for people who suffer from terrible, long-term pain.

Chemistry of a Natural Poison


The chemical formula for epibatidine is C11H13N2Cl. Notice that for every 11 carbon atoms in this compound, there are 13 hydrogen atoms, two nitrogen atoms and one chlorine atom. Once the internal arrangement of these atoms--known as the chemical structure--was determined (see the structure below), scientists realized how closely it resembled nicotine, a natural chemical compound with pain relief properties.

Many laboratories began to synthesize epibatidine and after studying it, scientists realized it was too toxic to be used as a pain-relieving drug. But they set out to tinker with the structure to see whether they could make a drug that could ease pain without producing toxic effects. That's just the kind of challenge that medicinal chemists and pharmacologists love. Medicinal chemists are scientists who synthesize new medicines. Pharmacologists are scientists who study the properties of medicines and their effects on the human body.

Chemical Structures of Epibatidine and ABT-594

Note the similarities between the structures of epibatidine and ABT-594.
ABT-594 is just one of the many compounds-potential pain relievers-that
was made by medicinal chemists "tinkering" with the structure of epibatidine.

With a little rearranging on the atomic level, epibatidine was morphed by medicinal chemists into several hundred new compounds--potential new pain relievers. One of them, ABT-594, pictured above next to the structure of epibatidine, appeared to reduce pain more effectively than the best products we have today. Unfortunately, tests of ABT-594 in humans found that it caused unwanted side-effects and so, the search continued for another compound based on the chemical structure of epibatidine. New versions are being tested currently and at least one of them may be the key to relieving the suffering of patients in years to come.

Cures From Nature

For thousands of years, nature, especially plant life, was the "pharmacy" from which people obtained their medicines. Even today it is estimated that 40 percent of all drugs contain at least one plant-derived ingredient1. The rain forests are natural chemical laboratories containing the richest variety of plant and animal compounds on Earth. Many new drugs are derived from the study of plants and animals of the rainforests. One day soon, we may owe a big debt of thanks to Epipedobates tricolor -a little rainforest frog--for providing Dr. Daly and other determined scientists with the "chemical inspiration" for a new, powerful pain-reducing drug. 

The Science
Center Salutes:
Dr. John Daly
Medicinal Chemist

Dr. John Daly is a scientist at the National Institutes of Health in Bethesda, Maryland. He has written more than 500 scientific research articles on medicinal chemistry and received many honors and awards for his work.

Dr. Daly's discovery of epibatidine in the rainforest of Ecuador and his search for a new pain reliever based on its chemistry demonstrates that he is a strong proponent of using natural products as a starting point for the development of drugs for the treatment of human illness.

In discussing his work, Dr. Daly called the small frogs of the rainforests "bioprospectors." By that he means that, through their diets, rainforest frogs pick up various novel compounds from insects, such as ants, millipedes and beetles, that are used by them for defense from predators, or other reasons that help them survive. He believes that such compounds are a great source of "chemical raw material" from which useful medicines may be developed for humans.

1Summner, J., (2000). The Natural History of Medicinal Plants Portland: Timber Press, Inc.

For a list of previous "Chlorine Compound of the Month" features, click here.


News & Resources

View our resource center to find press releases, testimonies, infographics and more.