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Review | Special issue | Vol 79, No. 1, 2009, pp.207-217
Published online, 10th December, 2008
DOI: 10.3987/REV-08-SR(D)5
Epibatidine: From Frog Alkaloid to Analgesic Clinical Candidates. A Testimonial to “True Grit”!

H. Martin Garraffo, Thomas F. Spande, and Michael Williams*

*Discovery Research, Cephalon Inc., 145 Brandywine Parkway, West Chester, PA 19380, U.S.A.

Abstract

A routine toxicity test of the alkaloid extract from the Ecuadoran poison frog Epipedobates anthonyi gave a Straub-tail (S-T) response on sub-cutaneous (sc) injection in mice, a phenomenon never seen before from any poison frog alkaloid. It is characteristic of opioids; however, in this instance it was not blocked by a morphine-antagonist, naloxone. Its site of action was soon shown to be a nicotinic receptor. The determination of the structure of this novel analgesic named epibatidine has led to a renaissance of research into controlling pain via nicotinic pathways (thereby minimizing the risk of tolerance/addiction) and the synthesis of many analogs, some of which are discussed.