Nicotine

• first found to bind to one variant of receptor.
• dampens pain
• weak analgesic (pain killer)
• causes serious side effects
• lung cancer
• heart disease

• John Daly (National Institute of Diabetes and Kidney Diseases) discovered Epibatidine - extract from the skin of a poisonous Ecuadorian frog - Epipedobates Tricolor - block pain in rats 200´ more effectively than morphine.

• compound very rare
• kept in freezer until some method of determining structure was found
• frog was endangered
• could not produce compound in captivity

• researchers used a new analytical tool - Nuclear Magnetic Resonance Spectroscopy
• structure of epibatidine found
• resembled nicotine, consistent with pain killing effect

• several research companies began to synthesise the compound
• Epibatidine - potent painkiller
• too toxic for humans

• Abbot laboratories in North Chicago worked on experimental drugs for Alzheimer’s disease
• discovered epibatidine was similar to their drugs
• selected ABT-594 for further testing

• lung depression
• constipation

physical dependence

Figure 1

The tropical frog Epipedobates tricolor is the original source of the chemical epibatidine, which Abbot chemists converted into the drug ABT-594. It has no natural enemies because a single tiny frog contains within its skin enough frightful chemistry to rub out a water buffalo!

NMR spectroscopy determined that the structures of nicotine and epibatidine resembled each other. This was concluded from its painkilling effect. The structure of ABT-594 was synthesised from the epibatidine compound.  The molecules can be seen in three-dimensions (Chime).

• proved as effective as morphine
• dampens pain from stimuli such as heat or stinging chemicals
• drug hinders the ability of nerve cells to fire in response to harmful mechanical and thermal stimuli
• does not hinder responses to benign sensations such as touch or mild heat

ABT-594 binds several hundred times more strongly to a nicotinic receptor from the central nervous system where neurones process pain information, compared to one that tells muscles to contract. For epibatidine ratio of above tests was about 57 to 1. This is because ABT-594 is less toxic than epibatidine.

ABT-594 appeared to be non-addictive. There are hopes that this is because it doesn’t act through the opioid receptors (through which morphine interacts), but nicotine is addictive.

1. Bannon, A.W. Journal of Science. 1998, Jan, 279, 77-81

2. Holladay, Mar W. J.Med Chem. 1998, Feb, 41, 407-417

3. http://communityhigh.org/classes/studentpub/WaterPollutants/umdl/chlorine/froggy