Epiquinamide: a poison that wasn't from a frog that was.
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, beta2-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.
Fitch
Richard W
RW
Department of Chemistry, Indiana State University, 600 Chestnut Street, Science S35E, Terre Haute, Indiana 47809, USA. rfitch@indstate.edu
Sturgeon
Gordon D
GD
Patel
Shaun R
SR
Spande
Thomas F
TF
Garraffo
H Martin
HM
Daly
John W
JW
Blaauw
Richard H
RH
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D000664:Amphibian Venoms / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D000818:Animals; D008401:Gas Chromatography-Mass Spectrometry; D015394:Molecular Structure; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D011898:Ranidae / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013034:Sparteine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000191:economics; D013237:Stereoisomerism; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D000664:Amphibian Venoms; D011807:Quinolizines; D011978:Receptors, Nicotinic; D013034:Sparteine; C481035:epiquinamide; C015971:lupinine; D000093843:Quinolizidine Alkaloids