Epibatidine
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| Systematic (IUPAC) name | |
| (1R,2R,4S)-(+)-6-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane | |
| Clinical data | |
| Pregnancy cat. | ? |
| Legal status | ? |
| Identifiers | |
| CAS number | 140111-52-0  |
| ATC code | ? |
| PubChem | CID 11031065 |
| DrugBank | DB07720 |
| ChemSpider | 10399316 |
| KEGG | C11690 |
| ChEMBL | CHEMBL298826 |
| Chemical data | |
| Formula | C11H13ClN2 |
| Mol. mass | 208.69 g/mol |
| SMILES | eMolecules & PubChem |
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Epibatidine is an alkaloid found on the skin of the endangered Ecuadorian frog, Epipedobates tricolor. These frogs, like other poison dart frogs, are best known for their ability to sequester poisons from their prey and secrete these poisons onto their backs.[1] Many Amerindian tribes would swipe the frogs' backs with their blowdarts to provide a much more successful hunt. The one toxin that distinguishes the Epipedobates tricolor from other frogs in this family is epibatidine. The frog uses the compound to protect itself from predators. Animals many times larger would die from the small amounts of epibatidine that the frog secretes. Epibatidine, which was being researched in 1974, turned out to be a very powerful analgesic. This had proven a powerful argument for further research, which has shown that epibatidine has gastrointestinal side effects. This gives the compound a very small therapeutic index and it is very unlikely to ever appear on the medicinal market.[2]
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[edit] History
John Daly, working for the National Institute of Health, collected samples of skin secretions from the frog in 1974. Although it was shown to work as an effective analgesic in mice with a potency 200 times that of morphine,[3] technology at the time was not able to discern the chemical's structure because the preserved sample was too small. In addition, Daly's research was hindered by the Convention on International Trade in Endangered Species of Wild Fauna and Flora, which put heavy restrictions on the collection of Epipedobates tricolor.
After further research in the late 90's, when technology finally allowed the determination of the compound's structure,[4] there was great excitement when epibatidine was found to be non-opioid. This was proven by Daly's experiment: administration of naloxone, an opioid antagonist, did not reverse epibatidine's effect.[5] Being a non-opioid suggested that it might have been a non-addictive compound with very few adverse effects. However, because of the small difference between therapeutic and toxic dose, epibatidine has never been used in humans.[6] Abbott Laboratories has produced derivatives of epibatidine in search of a less toxic analgesic with less side effects than opioids.[7]
[edit] Synthesis
Several total syntheses have been devised due to the relative scarcity of epibatidine in nature.[8] E. Tricolor frogs do not naturally possess epibatidine, but obtain epibatidine or its precursor from their surroundings. It has been suspected that the frog obtains its epibatidine or a precursor from is a flowery plant, since the similar toxin nicotine is also derived from this kind of source.[9] Locating the source is important, since epibatidine recovery from E. Tricolor frogs is made illegal after the frogs had been declared endangered. The population is still very unstable, and will not allow scientists to extract epibatidine in the near future.[10]
After the discovery of epibatidine's structure, more than fifty ways to synthesize epibatidine in the lab have been found successful. After a nine-step procedure, the substance was obtained as a racemate. The enantiomers could easily be separated with HPLC. The synthesis of epibatidine has brought a way to bypass the limitations of the substance's scarcity. It has proven to be quite productive, with a yield of about 40%.[5][11][12] There have also been successful attempts to create epibatidine-like molecules, like ABT-418 and epiboxidine. This was done in order to find an analgesic with less adverse effects.[9]
[edit] Structure and reactivity
Epibatidine’s structure is very similar to that of nicotine.[13] After this discovery in 1992, epibatidine had been proven to have similar bioactivation as its structural nephew. Other than its agonistic abilities to provide a similar antinociceptive response in vivo, epibatidine is no reactive compound. It is a hygroscopic oily substance that can act as a base, due to its nitrogenous aspects. Therefore, it can bind acids to form salts. Its structural resemblance to nicotine enables the substance to bind nicotinic acetylcholine receptors. However, the small difference in structure gives epibatidine a more powerful affinity to the receptors than nicotine. It acts as an acetylcholine agonist to invoke the release of dopamine and noradrenaline.[13] Ultimately, these components will cause analgesia at low doses.
Epibatidine can also bind to muscarinic acetylcholine receptors as an antagonist. This is, however, at a much lower affinity than to the nicotinic acetylcholine receptor. Binding to these receptors only occurs at a higher than therapeutic internal concentration: 8-16 µg kg−1. By disabling these postsynaptic neurons, paralysis will occur. When the nerves to vital organs get disrupted by epibatidine, death will certainly follow.[5]
[edit] Mechanism of action
Epibatidine has two mechanisms of action: it can bind either the nicotinic acetylcholine receptors (nAChR) or the muscarinic acetylcholine receptors (mAChR)[5]
- The analgesic property of epibatidine works by binding nicotinic acetylcholine receptor (nAChR) binding sites.
Nicotinic acetylcholine receptors are positioned in the postsynaptic membrane of nerve cells. They propagate neurotransmission in the central and peripheral nervous system. When neurotransmitters bind to these receptors the ion channel opens allowing Na+ and Ca2+ ions to move across the membrane. This depolarizes the post synaptic membrane inducing an action potential that will propagate the signal. This signal will ultimately induce a release of several substances among which are dopamine and norepinephrine, resulting in an antinociceptive effect on the organism. The usual neurotransmitter for nAChR is acetylcholine yet other substances like epibatidine and nicotine are able to bind the receptor as well and induce a similar, if not identical, response. Epibatidine has an extremely high affinity for nAChR’s and will induce a response at concentrations of ~10 µM. This is a 1000x lower concentration when compared to a nicotine induced response.[5]
- The paralytic property of epibatidine works by binding muscarinic acetylcholine receptors (mAChR)
These receptors are G-protein coupled of five subtypes. M2 and M4 are coupled to an inhibitory protein which impedes the functioning of adenylyl cyclase. This enzyme catalyses the reaction of ATP into cAMP, which is an important second messenger in a cell. M1, M3 and M5 are coupled to a Gq-protein, which will activate the phosphatidylinositol 3-kinases (PI3K). These enzymes will, when activated, catalyze the reaction of Phosphatidylinositol 4,5-bisphosphate (PIP2)into diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). These second messengers can affect several processes in the cell, such as (sarco) endoplasmic reticulum calcium ATP-ase (SERCA).
Low doses of epibatidine will only affect the nAChRs, due to a higher affinity to nAChRs than to mAChRs. Higher doses, however, will cause epibatidine to bind to the mAChRs and cause the paralytic effects.
[edit] Metabolism
Oddly enough, in vitro studies seem to suggest that epibatidine is hardly, if at all, metabolized in the human body.[14] Also there is currently little information on the path of clearance. Maximum concentration in the brain is about 30 minutes after injection and epibatidine is still present after 4 hours. This shows that the clearance has a low rate.[5] Speculations can be made as to how the metabolism of epibatidine works, since the large similarities with nicotine.[citation needed]
[edit] Toxicity
Epibatidine has several toxic consequences. Empirically proven effects include splanchnic sympathetic nerve discharge and increased arterial pressure.[13] The nerve discharge effects can cause antinociception partially mediated by agonism of central nicotinic acetylcholine receptors at low doses of epibatidine; 5 µg kg−1.[15] At higher doses, however, epibatidine will cause paralysis and loss of consciousness, coma and eventually death. The median lethal dose (LD50) of epibatidine lies between 1,46 µg kg−1 and 13,98 µg kg−1.[16] This makes epibatidine somewhat more toxic than dioxin (with an average LD50 of 22,8 µg kg−1). Due to the little difference between its toxic concentration and antinociceptive concentration, its therapeutic uses are very limited.
Epibatidine is a rare compound in nature and since it appears to serve no useful medical uses, it will not be produced in the near future. Epibatidine does not pose any threat to the environment whatsoever.
[edit] Efficacy and side effects
Epibatidine has a high analgesic potency, as stated above. Studies show it has a potency at least 200 times that of morphine.[5] As the compound was not addictive nor did it suffer the effects of habituation, it was very promising to replace morphine as a painkiller. Unfortunately for its therapeutic uses, the therapeutic concentration is very close to the toxic concentration. This means that even at a therapeutic dose (5 µg kg−1[15]) some of the epibatidine might bind the muscarinic acetylcholine receptors and cause adverse effects, such as hypertension, bradycardia and muscular paresis.[13] There has been a significant amount of research towards creation of a derivative of epibatidine characterized by reduced toxicity, whilst retaining the powerful analgesic effect[9]. To date these efforts remain unsuccessful, but epibatidine and its relatives may still have a role in pain management in the future.
[edit] Effects on animals
In research on mice, administration of doses over 5 μg kg-1 of epibatidine caused a dose-dependent paralyzing effect on the organism. With doses over 5 μg kg-1, symptoms included hypertension (increased blood pressure), paralysis in the respiratory system, seizures, and, ultimately, death. The symptoms do, however, change drastically when lower doses are given. Mice became resistant to pain and heat with none of the negative effects of higher doses. Compared to the gold standard in pain management, morphine, epibatidine needed only 2.5 μg kg−1 to initiate a pain-relieving effect whilst the same effect required approximately 10 mg kg−1 of morphine. Currently, only rudimentary research into epibatidine's effects has yet been performed; the drug has been administered only to rodents for analysis at this time.[12]
[edit] References
- ^ Daly, J.W., Gusovsky, F., Myers, C.W., Yotsuyamashita, M., and Yasumoto, T. (1994). "1st Occurrence of Tetrodotoxin in a Dendrobatid Frog (Colostethus-Inguinalis), with Further Reports for the Bufonid Genus Atelopus."Toxicon 32 (3): 279–285. doi:10.1016/0041-0101(94)90081-7. PMID 8016850.
- ^ Prince and Sine; Sine, SM (2008). "Epibatidine activates muscle acetylcholine receptors with unique site selectivity"Biophysical Journal (Biophysical Journal) 75 (4): 1817–27. doi:10.1016/j.soildyn.2007.11.006. PMC 1299853. PMID 9746523. http://www.biophysj.org/cgi/content/full/75/4/1817. Retrieved 2008-10-10.
- ^ William Wells. One Frog's Poison Retrieved December 24, 2010.
- ^ Suzanne Strong. 1998. Altering Chemistry: Epibatidine a Novel Alkaloid
- ^ a b c d e f g J.R. Traynor, Epibatidine and pain, British Journal of Anaesthesia 1998, 81: 69-76, [1]
- ^ Diana L. Donnelly-Roberts, Pamela S. Puttfarcken, Theresa A. Kuntzweiler, Clark A. Briggs, David J. Anderson, Jeffrey E. Campbell, Marietta Piattoni-Kaplan, David G. Mckenna, James T. Wasicak, Mark W. Holladay, Michael Williams and Stephen P. Arneric. 1998. ABT-594 [(R)-5-(2-Azetidinylmethoxy)-2-Chloropyridine]: A Novel, Orally Effective Analgesic Acting via Neuronal Nicotinic Acetylcholine Receptors: I. In VitroCharacterization Retrieved December 24, 2010.
- ^ Deriving a non-opiate painkiller [ABT-594] from Epipedobates tricolor
- ^ Olivo, Horacio F.; Hemenway, Michael S. (2002). "Recent syntheses of epibatidine. A review"Organic Preparations and Procedures International 34 (1): 1–26. doi:10.1080/00304940209355744.
- ^ a b c Matthew J. Dowd, 1999, 'Epibatidine'
- ^ Red List of the International Union for the Conservation of Nature (IUCN), [2]
- ^ Clayton, S.C.; Regan, A.C. Total Synthesis of (+/-)-Epibatidine. Tetrahedron Lett. 1993,34, 7493-7496.
- ^ a b Broka, C.A. Synthetic Approaches to Epibatidine. Med. Chem. Res. 1994, 4, 449-460.
- ^ a b c d M. Fisher, D. Huangfu, T.Y. Shen, P.G. Guyenet, J. Pharmacol. Exp. Ther. 270 (1994) 702.[3]
- ^ Watt A. P., Hitzel L., Morrison D., Locker K. L., Determination of the in vitro metabolism of (1)- and (2)-epibatidine, Journal of Chromatography A; 896: 229–238, 2000.
- ^ a b Badio B, Daly JW. Epibatidine,a potent analgetic and nicotinic agonist, Molecular Pharmacology 1994; 45: 563-569
- ^ Sihver, Acta Neurologica Scandinavica, Ligands for in vivo imaging on nicotinic receptor subtypes in Alzheimer brain, 2002 [4]
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