Painkillers

Mick Bajcar
November 98

Imagine a painkiller 200 times more powerful than morphine but without the side effects of conventional painkillers! And, what is more, a compound that may hold hope in the future for sufferers from Alzheimer's Disease! 

The key to the mystery lies in the heart of South America, in one of the toxic substances secreted by the Poison-arrow frog Epipedobates tricolor. This is currently under investigation by Dr. John Malpass, University of Leicester Chemistry Department. Discovered as recently as 1992 the compound, called epibatidine, fired the enthusiasm of many researchers because of its medical implications and unusual structure. 

Being the first natural product that has this particular structural type, it has now been made in the laboratory by a number of research groups so that there is no longer any need to work with the frogs themselves. Unfortunately 750 frogs were killed to extract the toxin at first as each frog only yielded 100ug of the chemical.

The naturally-occurring compound, epibatidine, cannot be used safely since it also has toxic properties. Dr. Malpass sees the design of more potent and selective variants as the way ahead. He is co-operating with a major pharmaceutical company in testing new compounds made at Leicester and is developing ways of extending the range of compounds available and modifying their properties. Early assays show that the major new variant ('homoepibatidine') is as active as epibatidine itself. 

The research team has made compounds in which parts of the epibatidine structure are grafted onto molecular fragments. This is similar to those found in natural products from well-known plants such as deadly nightshade and Coca. The new compounds are made in steps from simple chemicals and the frogs themselves are not involved at all.

Already, researchers have discovered that epibatidine acts in a completely different way from morphine and other opiates. This has led to the exciting possibility that it may hold a clue to reducing the symptoms of Alzheimer's disease. The particular site in the central nervous system (receptor) which is targeted by nicotine may hold the key. 

Despite its addictive and toxic nature, nicotine has a number of very positive properties in terms of brain functions such as memory and cognition. It can also reduce the effects of Alzheimer's Disease. Surprisingly, epibatidine is much better than nicotine itself at binding to this key receptor, hence the search for even more active compounds is under way.

Speaking of his research, Dr. Malpass said, "We have been working with compounds very close to Epibatidine for many years. Nature still holds many secrets and the discovery of this powerful small molecule from a tiny frog has given our own work a tremendous boost in the search for therapeutically useful compounds."

From Dr. Malpass via Mick Bajcar: The frogs do not produce epibatidine when reared in captivity, suggesting that they must derive the toxin from something in their diet (Chemistry in Britain, 1996, John Emsley).