Epipedobates tricolor Epibatidine

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-... 

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]. 

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... 

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... 

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]. 

Epibatidine, exo-2-(6-chloro-3-pyridile-7-azabicyclo[2.2. 1]heptane, the structure of which is shown below, is an alkaloid extracted from the skin of the Ecuadorian frog, Epipedobates tricolor. This alkaloid has been reported to possess potent, non-opioid, analgesic properties. In order to investigate the physiological properties in more detail Watt et al. [2], synthesized Ae material and also developed an analytical procedure for identifying and measuring the enantiomers present in the natural product. 

However, Daly was only able to elucidate the structure of epibatidine in 1992 by meanwhile considerably upgraded NMR spectroscopy. [548] The structure was a surprise it contained a 7-azabicyclo[2.2.1]heptane skeleton, something without precedent at that time in Nature, and a 2-chloropyridyl moiety, likewise rare in natural products. Interestingly, Epipedobates tricolor does not synthesise epibatidine by itself, but picks up the alkaloid with food from an unknown source. Frogs, which are bred in captivity, do not contain epibatidine. 

Epibatidine, a colorless oil isolated from the skin of the Ecuadorian poison frog Epipedobates tricolor, has several times the analgesic potency of morphine. It is the first chlorine-containing, nonopioid (nonmorphine-like in structure) analgesic ever isolated from a natural source (See Example 10.6)... 

Alkaloids with affinity for nAChRs have been isolated from the frog, Epipedobates tricolor (Dendrobatidae). Most pharmacological studies have focused on one of these alkaloids, epibatidine (35), as it is antinociceptive and toxic, with selectivity for 014P2 > 3P4 > 7, nAChRs numerous synthetic... 

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