Epibatidine discovery

Badio B, Garraffo HM, Spande TF, Daly JW Epibatidine discovery and definition as a potent analgesic and nicotinic agonist. Med Chem Res 4 440, 1994... 

Daly, J.W. GarrafTo, H.M. Spande, T.F. Decker, M.W. Sullivan, J.P. Williams, M. (2000) Alkaloids from frog skin the discovery of epibatidine and the potoitial for developing novel non-opioid analgesics. Nat. Prod. Rep., 17, 131-5. 

Identification of a natural compound as the first potent nicotinic analgesic -discovery of EPIBATIDINE... 

Elucidation of the structure of epibatidine - more than a decade after its initial discovery... 

The natural product epibatidine was the starting point for worldwide activities towards the discovery of nicotinic analgesics. Besides its unusual antinociceptive potency (review Bai et al., 1997) its exceptional structure combines a scarce chloropyridine moiety with a 7-aza-norbornane (7-azabicyclo[2.2.1]heptane) bicycle which has never before been found in a natural product before. In 1994 the absolute configuration of natural (+)-epibatidine was determined to be IR RAS (Fletcher et al., 1994). Initial patents on epibatidine and close structural analogs were filed by the U.S. Department of Health (Daly et al., 1993, 1995). 

The properties of ABT-594, the most advanced compound derived from the discovery of epibatidine, are well documented in the literature (Decker et al., 1998 Thatte, 2000). Its antinociceptive potential has been proven in various animal models, but according to Boyce et al. (2001) the side-effect profile of ABT-594 does not represent a significant improvement compared to other potential nicotinic analgesics. 

The neonicotinoids were not generated through lead-optimisation of natural products, eg. nicotine or epibatidine, but of nitro-substituted ketene aminals, a serendipitous discovery. 

Epipedobates tricolor. Epibatidine was found to be an analgesic that is 200 times more potent than morphine. Further studies indicated that epibatidine and morphine bind to different receptors. This discovery is very exciting, because it means that epibatidine can serve as a new lead compound. Although this compound is too toxic for clinical use, a significant number of researchers are cur-... 

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