By John Cameron and Kathleen Brawley

Department of Chemistry   University of Aberdeen


In 1932,  scientists first realise it is possible to block pain,  by targeting the acetylcholine receptors, which blocks pain.

Nicotine

  • first found to bind to one variant of receptor.
  • dampens pain
  • weak analgesic (pain killer)
  • causes serious side effects
  • lung cancer
  • heart disease
No further progess using the acetylcholine receptor in developing an analgesic until………….

 
 
In 1976
  • 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.
Research Halted
  • compound very rare
  • kept in freezer until some method of determining structure was found
  • frog was endangered
  • could not produce compound in captivity
In 1986 
  • researchers used a new analytical tool - Nuclear Magnetic Resonance Spectroscopy
  • structure of epibatidine found
  • resembled nicotine, consistent with pain killing effect

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

 
ABT-594 Selected
  • 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
In 1998 ABT-594 appears to be many times more powerful than morphine without the serious side effects.
  • 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!


 
Figure 2

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).


 
 
ABT-594
  • 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

 
Toxicity Tests on membranes Containing Acetylcholine Receptors

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.


 
Addictive tests on membranes containing acetylcholine receptors

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.


 
References

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
 

Department of Chemistry    University of Aberdeen
Web page originally hosted by University of Aberdeen, written and last updated Sept 2000.

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