Epibatidine

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Not to be confused with Eptifibatide.
Epibatidine
Epibatidine structure.png
Systematic (IUPAC) name
(1R,2R,4S)-(+)-6-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane
Clinical data
Identifiers
140111-52-0 YesY
PubChem CID 11031065
DrugBank DB07720 YesY
ChemSpider 10399316 YesY
KEGG C11690 N
ChEMBL CHEMBL298826 YesY
Chemical data
Formula C11H13ClN2
208.69 g/mol
 N (what is this?)  (verify)

Epibatidine is a strong toxic alkaloid that is secreted Epipedobates anthonyi (also known as Epipedobates tricolor)[1] which live in central and southern Ecuador. It was discovered by John W. Daly in 1974 and its structure was elucidated in 1992.[2]

Epibatidine's toxicity stems from its ability to bind and turn on nicotinic and muscarine acetylcholine receptors. These receptors are involved in the transmission of painful sensation and in movement, among other functions. By binding and turning on specific receptors, epibatidine causes numbness and eventually paralysis. Doses are lethal when the paralysis causes respiratory arrest. Originally it was thought that epibatidine could be useful as a drug but because it can be deadly even at very low doses it is no longer being researched for potential therapeutic uses.[3]

History[edit]

Epibatidine was discovered by John W. Daly in the 1970s. It was isolated from the skin of Epipdobates anthonyi frogs collected by Daly and a colleague of his, Charles Myers. Between 1974 and 1979 Daly and Myers collected the skins of nearly 3000 frogs from various sites in Ecuador after finding that a small injection of a preparation from their skin caused analgesic (painkilling) symptoms in mice with symptoms that resembled those of an opioid.[2] In spite of its common name—Anthony’s Poison Arrow frog—suggesting that it was used by natives when hunting,[4] a paper written by Daly in 2000 claimed that there was no local folklore or folk medicine surrounding the frogs and that they were considered largely unimportant by the locals.[5]

A photo of a Epipedobates tricolor on a leaf
Epipedobates tricolor on a leaf

It took until 1992 for epibatidine’s structure to be determined, an effort hindered by E. anthonyi gaining protected status by the Convention on International Trade in Endangered Species in 1984.[5] Furthermore, it wasn’t possible to breed the frogs to harvest more of the compound because there is no epibatidine present on the skins of E. anthonyi raised in captivity. The frogs do not produce the chemical themselves; instead they isolate it from their diet and then sequester it on their skin. The likely source is beetles, ants or mites that they eat.[6] In spite of these difficulties the structure was eventually determined and the first synthesis of epibatidine was completed soon after (in 1993). There have been numerous other syntheses have been developed since.[5]

There was intense interest in epibatidine’s use as a drug because while it functioned as a painkiller it was found not to be an opioid.[2] This meant that it could be used without the danger of habituation that accompanies the use of painkillers like morphine. However it cannot be used in humans because the dose resulting in toxic symptoms is too low for it to be safe.[7]

Synthesis[edit]

The chemical synthesis of epibatidine after Corey

Several total syntheses routes have been devised due to the relative scarcity of epibatidine in nature.[8]

After the discovery of epibatidine's structure, more than fifty ways to synthesize epibatidine in the lab have been devised. A nine-step procedure produces the substance as a racemate (in contrast, the naturally occurring compound is the (+)-enantiomer; the (−)-enantiomer is not naturally occurring). It was later determined that the (+) and (-) enantiomers had equivalent analgesic as well as toxic effects. The process has proven to be quite productive, with a yield of about 40%.[9][10][11]

Synthetic analogues[edit]

Abbott Laboratories has produced derivatives of epibatidine, like ABT-594, in search of a less toxic analgesic with less side effects than opioids.[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.[13]

There has been a significant amount of research towards the creation of a derivative of epibatidine characterized by reduced toxicity, whilst retaining the powerful analgesic effect.[13] To date these efforts remain unsuccessful.

Chemical Structure[edit]

Epibatidine (C11H13ClN2 208.6901) is a piperidine alkaloid with a structure similar to that of nicotine.[14] It is a hygroscopic oily substance which is a base, due to its nitrogen.

Biological Effects[edit]

Mechanism of Action[edit]

Epibatidine has two mechanisms of action: it can bind either the nicotinic acetylcholine receptors (nAChR) or the muscarinic acetylcholine receptors (mAChR)[9]

  • The analgesic property of epibatidine is believed to pass through by binding to α4/β2 nicotinic receptors. Epibatidine also binds to α3/β4 and to much lesser extent α7 receptors (affinity 300-fold less than for α4/β2)[15] The rank order of affinities is αε > αγ > αδ.[16]

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.[9]

  • 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.

Both (+)- and (-)enantiomers of epibatidine are biologically active, and both have similar binding affinities to nAChRs[9]

Symptoms[edit]

Epibatidine has several toxic consequences. Empirically proven effects include splanchnic sympathetic nerve discharge and increased arterial pressure.[14] 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.[17] 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.[18] 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.

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.

Pharmacology[edit]

Epibatidine most effectively enters the body through injection.[19] Oddly enough, in vitro studies seem to suggest that epibatidine is hardly, if at all, metabolized in the human body.[20] 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.[9]

Medical Uses[edit]

Epibatidine has a high analgesic potency, as stated above. Studies show it has a potency at least 200 times that of morphine.[9] As the compound was not addictive nor did it suffer the effects of habituation,[citation needed] 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[17]) some of the epibatidine might bind the muscarinic acetylcholine receptors and cause adverse effects, such as hypertension, bradycardia and muscular paresis.[14]

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 (4,000 times the efficacy.) 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.[11]

Antidote[edit]

Its antidote is mecamylamine (Inversine),[21] a nicotinic acetylcholine receptor antagonist that is nonselective and noncompetitive.[22]

See also[edit]

References[edit]

  1. ^ Fitch, R. W.; Spande, T. F.; Garraffo, H. M.; Yeh, H. J. C.; Daly, J. W. (2010). "Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog Epipedobates anthonyi⊥". Journal of Natural Products 73 (3): 331–7. doi:10.1021/np900727e. PMC 2866194. PMID 20337496.  edit
  2. ^ a b c "Epibatidine: From Frog Alkaloid to Analgesic Clinical Candidates. A Testimonial to "True Grit"!" (PDF) (79(1)). Heterocycles. pp. 207–217. Retrieved 2015-05-06. 
  3. ^ Schwarcz, Joe (2012). The Right Chemistry. Random House. 
  4. ^ "Epipedobates anthonyi". Retrieved 2015-05-06. 
  5. ^ a b c Daly and Garraffo. "Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics". The Royal Society of Chemistry 17: 131–135. doi:10.1039/a900728h. 
  6. ^ Elizabeth Norton Lasley. "Having Their Toxins and Eating Them Too Study of the natural sources of many animals' chemical defenses is providing new insights into nature's medicine chest" 45 (12). Oxford Journals. pp. 945–950. Retrieved 2015-05-06. 
  7. ^ 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. Arneric1. "ABT-594 [(R)-5-(2-Azetidinylmethoxy)-2-Chloropyridine]: A Novel, Orally Effective Analgesic Acting via Neuronal Nicotinic Acetylcholine Receptors: I. In VitroCharacterization" 285 (2). The Journal of Pharmacology and Experimental Therapeutics. pp. 777=786. 
  8. ^ 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. 
  9. ^ a b c d e f "Epibatidine and pain" (PDF) 81. British Journal of Anaesthesia 1998. pp. 69–76. Retrieved 2014-03-12. 
  10. ^ Clayton, S.C.; Regan, A.C. Total Synthesis of (+/-)-Epibatidine. Tetrahedron Lett. 1993,34, 7493-7496.
  11. ^ a b Broka, C.A. Synthetic Approaches to Epibatidine. Med. Chem. Res. 1994, 4, 449-460.
  12. ^ "Deriving a non-opiate painkiller [ABT-594] from Epipedobates tricolor". Mongabay.com. Retrieved 2014-03-12. 
  13. ^ Cite error: The named reference Dowd was invoked but never defined (see the help page).
  14. ^ a b c Fisher M, Huangfu D, Shen TY, Guyenet PG (1994). "Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent.". J Pharmacol Exp Ther 270 (2): 702–7. PMID 8071862. 
  15. ^ British Journal of Anaesthesia, 1998; 81: 69-76
  16. ^ Richard J. Prince and Steven M. Sine (1998-04-03). "Epibatidine Binds with Unique Site and State Selectivity to Muscle Nicotinic Acetylcholine Receptors". Jbc.org. Retrieved 2014-03-12. 
  17. ^ a b Badio B, Daly JW. Epibatidine,a potent analgetic and nicotinic agonist, Molecular Pharmacology 1994; 45: 563-569
  18. ^ Sihver, Acta (2002). "Neurologica Scandinavica, Ligands for in vivo imaging on nicotinic receptor subtypes in Alzheimer brain". Interscience.wiley.com. Retrieved 2014-03-12. 
  19. ^ Sullivan, J.P. and Bannon, A.W. "Epibatidine: Pharmacological Properties of a Novel Nicotinic Acetylcholine Receptor Agonist and Analgesic Agent". CNS drug reviews 2 (1): 21–39. 
  20. ^ 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.
  21. ^ Damaj, M.I. et. al. "Pharmacological effects of epibatidine optical enantiomers". Brain Research 664 (1): 34–40. 
  22. ^ Bacher, I. et al. "Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders". Expert Opinion on Pharmacotherapy 10 (16): 2709–2721. doi:10.1517/14656560903329102. 

External links[edit]