Story of the month

A natural frog poison with pain-killing potential

Suppose you are a native of the Colombian tropical rainforest and want to go hunting efficiently. Quickly kill or at least paralyse your prey with the only weapon you have: a blow dart. Well, you could dip your arrow tips in a strong poison.  

These natives actually have been doing this for centuries. They rub the tips of their darts on the skin of a tiny frog, aptly nicknamed the "poison-dart" frog.  In doing so, they coat the dart tips with a toxin that, even in small amounts, can paralyse and kill animals.  In fact, the toxin generated by just one of these frogs would be enough to kill a huge water buffalo, thousands of times froggy's size.

 "Very intriguing", is what Dr John Daly (US National Institutes of Health) found. (This is, by the way, the general feeling that drives all scientists: finding things "intriguing"). He and his scientific team analysed the toxins found in the skin of another frog, this time from Ecuador, called Epipedobates tricolor. 

They determined that one of the eighty or so toxins in the frog skin - which they named "epibatidine" - appeared to be 500-1000 times more powerful than the morphine for pain relief.

Unfortunately, the amount of epibatidine - less than 0.001g - isolated by the team was not sufficient to analyse completely.  And because Epipedobates tricolor was then declared endangered species, scientists were unable to obtain any additional frogs.  A small sample of epibatidine was frozen for safekeeping in their laboratory and about a decade later, methods became available to chemically analyse such minute quantities.  Dr Daly's determination to understand the frog toxin may one day result in relief for people who suffer from severe, long-term pain.

Chemistry of a natural poison

Now, let's talk some chemistry here. The chemical formula for the chlorine-containing epibatidine is C₁₁H₁₃N₂Cl.  Wow, that tells you a lot… But close examination of the chemical structure of these atoms revealed that it closely resembles nicotine, a natural chemical with pain relieving properties. And of course: the atom Cl in the structure is a chlorine atom.

Many laboratories began to synthesise epibatidine and after studying it, scientists concluded that it was too toxic to be used as a pain-relieving drug.  What chemists do when a molecule looks very promising but unsuited in its present form is to set out a programme for introducing slight chemical changes to the types of atoms they contain, to the structure or to both.

Through rearrangements on the atomic level, epibatidine was morphed by medicinal chemists into several hundred potential new pain relievers. One of them, ABT-594 appeared to reduce pain more effectively than the best products available today.  Unfortunately, tests of ABT-594 in humans resulted in undesirable side-effects, so the search for an alternative continues. New versions based on epibatidine continue to be tested, and may potentially relieve severe pain in years to come.

The man with whom this frog- story started, Dr John Daly, is a medicinal chemist. He has written more than 500 scientific research articles on medicinal chemistry and received many honours and awards for his work.  He is a strong proponent of using natural products as a starting point for the development of human medicines.  

Text based on the original produced by the Chlorine Chemistry Council (US). For additional information, read Euro Chlor's Science Dossier on Natural Organohalogens

[Image courtesy of Jan Verkade]