Introduction

Epibatidine is a potent analgesic of the alkaloid family of drugs. It was first isolated from a frog (Epipedobates tricolor) found in the rain forests of Equador by Dr. John Daly of the National Institutes of Health in the USA in 1974. Using the Straub tail response test on mice it was found to be 200 times as effective as morphine. However only about 750 millgrams was ever extracted from this rare type of frog, and political reasons made it impossible to go back and juice more of them to extract the compound. When in the 1980's an international treaty banned the collection of many species, including this frog, Daly was forced to try and breed the frogs in captivity. Although the frogs survived, their skins did not contain the the compound with the analgesic effect. It is possible therefore the frogs do not biochemically produce it, but may ingest it in their natural habitat, extracting then secreting it.In the 1970's and 1980's analytical hardware was not advanced enough to be able to elucidate the structure of this strange compound (alkaloid 208/210 as Daly termed it). With all other avenues closed to him, Daly put his remaining sample on ice until technology had advanced enough to be able to solve his problems. By the 1990's NMR technology had progressed to the stage where the chemical structure could be unambiguously be shown to be as shown below.

Structure

Here's the chemical structure of epibatidine; both of the pictures show the same structure, the first being drawn topologicaly correct and the second is drawn to help show it's conformation in space a bit better. It's the bridging nitrogen the the 6-membered ring that causes the problem, in the second picture one of the bridging bonds is shown with a dotted line, to represent it being behind the bond it appears to cross.. Also the molecule can exist in +- isomers, and the structure shown should perhaps more correctly be labeled as (+/-) epibatidine.

One of the first published syntheses was by Clayton and Regan (A.C. Total Synthesis of (+/-)-Epibatidine. Tetrahedron Letters 1993, 34, 7493-7496.)

         /|\
        / | \
       /  |  \
      |   |   |  H
      |   NH  | /
      |   |   |/   /\\
       \  |  / \  /  \\
        \ | /   \/    \\
         \|/    ||      |
                ||      |
                ||      |
                 \     /\
                  \   /  \
                   \N/    Cl




       C      C
      / \    /|  H
     /   \  / | / 
    /     C   |/
    C     :   C     /\\
    \     : /   \  /  \\
     \   : /     \/    \\
      \  :/      ||      | 
       C/:       ||      |   
        \:       ||      |
         N        \     / \  
         |         \   /   \
         |          \N/     Cl
         H

Mechanism

Once a synthesis of epibatidine had been perfected, enough compound was available to study how it actually worked to kill pain in animals. Treatment of mice with an opiate antagonist (naxalone), which should stop any opiate drugs from working, did not lessen epibatidines pain killing effect. This proved that although Daly's initial Straub test suggested it was an opiate (because it was so powerful) it must in fact work in a different manner. Further work proved that it in fact bound to nicotinic acetylcholine receptors, a completely different machanism to all other previously found (useful) painkillers. In fact giving a nicotinic antagonist (e.g. mecamylamine) does block the pain killing effect; at least in the central nervous system, but interestingly not the peripheral nervous system. Indeed molecular modeling shows epibatidine is similar in shape to nicotine, but it binds to the receptor at far lower concentrations(Ki=0.043-0.055 nM).

Often activity is dependent on the stereochemistry of the drug, for instance the natural nicotine isomer (S-(-)-nicotine) is binds 20 times as strongly as some of the synthesised isomers. With epibatine however the activity of all the isomers is (roughly) equivalent. Molecular modeling can again show why the interaction of the nicotine is stereospecific and epibatine is not; the isomers of nicotine occupy different volumes in space, but the isomers of epibatidine do not.

Unfortunately, epibatidine is even more toxic than nicotine; which is only to be expected for a molecule that binds to a nicotinic cholinergic receptor. Symptoms include an increase in heart rate and blood pressure, convulsions, paralysis and death with increasing dose. And herein lies the reason you will find so much in the scientific literature about epibatidine, if an analgous compound be found that has the pain killing properties, without the side effects, we'd have a powerful analgesic that would be as good as morphine, but without the addiction and withdrawal problems. One of the most promising analogues, called ABT-594 has an effect 30-70 times stronger than morphine (in rat tests anyway) without morphine like withdrawal symptoms. Only testing in humans will discover wether ABT-594 gives a hit, and similar addiction, to that of cigarettes!

Primary Sources

Altering Chemistry: Epibatidine a Novel Alkaloid By Suzanne Strong :- http://wwwchem.csustan.edu/chem4400/sjbr/strong98.htm
Epibatidine By Matthew J. Dowd :- http://www.phc.vcu.edu/feature/epi/