Epiquinamide: A Poison That Wasn’t from a Frog That Was

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2009-02, Vol.72 (2), p.243-247
• Main Authors: Fitch, Richard W, Sturgeon, Gordon D, Patel, Shaun R, Spande, Thomas F, Garraffo, H. Martin, Daly, John W, Blaauw, Richard H
• Format: Article
• Language: English
• Subjects: acetamidoquinolizidine; agonists; alkaloids; Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - toxicity; Amphibian Venoms - chemical synthesis; Amphibian Venoms - chemistry; Amphibian Venoms - isolation & purification; Amphibian Venoms - toxicity; Animals; Anura; Biological and medical sciences; chemical reactions; epibatidine; Epipedobates tricolor; epiquinamide; frogs; Gas Chromatography-Mass Spectrometry; General pharmacology; Medical sciences; Molecular Structure; nicotinic acetylcholine receptor; nitroquinolizidine; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; quinolizidine alkaloids; Quinolizines - chemical synthesis; Quinolizines - chemistry; Quinolizines - isolation & purification; Quinolizines - toxicity; Ranidae - metabolism; receptors; Receptors, Nicotinic - drug effects; Sparteine - analogs & derivatives; Sparteine - chemical synthesis; Sparteine - chemistry; Sparteine - economics; Stereoisomerism; stereoisomers
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np8005452

In 2003, we reported the isolation, structure elucidation, and pharmacology of epiquinamide (1), a novel alkaloid isolated from an Ecuadoran poison frog, Epipedobates tricolor. Since then, several groups, including ours, have undertaken synthetic efforts to produce this compound, which appeared initially to be a novel, β2-selective nicotinic acetylcholine receptor agonist. Based on prior chiral GC analysis of synthetic and natural samples, the absolute structure of this alkaloid was established as (1S,9aS)-1-acetamidoquinolizidine. We have synthesized the (1R*,9aS*)-isomer (epi-epiquinamide) using an iminium ion nitroaldol reaction as the key step. We have also synthesized ent-1 semisynthetically from (−)-lupinine. Synthetic epiquinamide is inactive at nicotinic receptors, in accord with recently published reports. We have determined that the activity initially reported is due to cross-contamination from co-occurring epibatidine in the isolated material.