Epipedobates tricolor

Keywords Epibatidine analogues, Epipedobates tricolor, Domino Heck reaction, frog, synthesis... 

One of these natural products, epibatidine (1) was isolated from the skin of the Ecuadorian frog, Epipedobates tricolor, by Daly and coworkers in 1992 and found to have powerful analgesic activity and high binding affinity to nicotinic acetylcholine receptors (uAChRs). This is reminiscent of a classical apphcation of nicotine (2), being stractmally related to 1 [3]. 

Figure 8 Venomous animals with chemotherapeutic potential, (a) Vampire bat (Desmodus rotundas (http // www.Animalpicturesarchive.com)) (b) medicinal leech [Hirudo medicinalis)-, (c) oriental fire-bellied toad (Bombina orientalis)-, (d) phantasmal poison frog [Epipedobates tricolor), (e) solitary tunicate sea peach Halocynthia aurantium), (f) glia monster (Heloderma suspectum). Photos (b)-(f) by I. Boyd (Creative Commons Attribution ShareAlike License), H. Van (Public domain), L. Ghoul (Creative Commons Attribution ShareAlike License), A. Rode (Creative Commons Attribution ShareAlike License) and Arpingstone (Public domain), respectively. See website for photo credit (a).

Epibatidine (5, Figure 11.5), a natural alkaloid isolated by Daly et al.55 from the Ecuadorian poison dart frog, Epipedobates tricolor, has recently proved that the proposed pharmacophores are not complete. Epibatidine is the most potent central nicotinic receptor ligand reported to... 

Only in 1990 were the remains of the original extract stored by Daly subjected to modern analytical methods and the structure of the compound - which was named epibatidine - finally elucidated by spectroscopic methods, especially IR and NMR techniques (Spande et al., 1992 Daly, 1993 Daly et al., 2000). This was published in 1992 -12 years after the initial publication on Epipedobates tricolor extracts (Daly et al., 1980) and very shortly after Daly and co-workers had filed patents on epibatidine and close structural analogs (see Epibatidine). 

An alkaloid, epibatidin (173), has been isolated from skin of the Ecuadorian frog Epipedobates tricolor which exhibited a 200-fold potency compared with morphine as an analgesic in the Straub-tail test. Extracts from 750 frogs provided only 1 mg of the Straub-tail alkaloid. The researchers had to wait for a decade until more sensitive instruments... 

In the last of the natural product papers published in the Journal of Natural Products of which the author is aware, Daly and co-workers utilized bioassay-guided techniques to direct the isolation of a novel quinolizidine alkaloid, epiquin-amide (86) from the Ecuadorian poison frog Epipedobates tricolor.166... 

Several note vorthy halogenated terrestrial alkaloids are known, with epibatidine (104) at the top of the list [88]. This apparent frog Epipedobates tricolor) metabolite has powerful analgesic activity [89] and an intensive search is underway for a clinically useful drug [90]. A few chlorinated plant alkaloids have also been discovered. Romucosine F (lOS) is present in Annora purpurea, a South American bushy tree [91], and the closely related romucosine B (106) is found in the stems of RolUnia mucosa [92]. The furoquinoline alkaloid chlorodesnkolbisine (107) was isolated from the African folk medicine plant Teclea nobilis [93]. The authors of this latter study provide convincing evidence that 107 is not an isolation artifact (e.g. from the corresponding epoxide with HCl). 

The biological activity of epibatidine has not been studied in any detail because of the minute quantities available from the frog Epipedobates tricolor. Its presence as a trace alkaloid and its chromatographic purification were based on the Straub tail response that epibatidine causes in mice. The Straub tail response is characteristic of opiate alkaloids however, unlike that caused by morphine and other opiates, the response caused by epibatidine was not reversed by the opiate antagonist naloxone (765). Epibatidine proved to be a potent analgetic, being manyfold more potent than morphine in the hot plate analgetic assay (765). Epibatidine had very low affinity for opioid receptors (765). 

The alkaloid epibatidine (56) was discovered from the skin of an Ecuadorian poison frog Epipedobates tricolor), and its... 

South American frog, Epipedobates tricolor, is 200-400 times more potent than morphine as an analgesic (118). 

Epibatidine (9.48) is a potent analgesic from the Ecuadorian poison frog Epipedobates tricolor,408 Although the compound itself is too toxic to use as a drug, an analogue developed by Abbott Laboratories (9.49) is less toxic, nonaddictive, and as effective as morphine.409... 

Epibatidine (112) was isolated from skin extracts of the Ecuadoran poison frog Epipedobates tricolor. Its structure was determined using MS, IR, UV, and NMR on 112 and the V-acetyl derivative of 112 [322]. 

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