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Epibatidine
Systematic (IUPAC) name
(1S,4R,6R)-6-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane
Identifiers
CAS number 140111-52-0
ATC code  ?
PubChem 11031065
ChemSpider 746409
Chemical data
Formula C11H13ClN2
Mol. mass 208.69 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

Epibatidine is an alkaloid that originally is found in the skin of a neotropical poisonous frog, Epipedobates tricolor, found in Ecuador.

It was initially isolated by John Daly at the National Institutes of Health, and was found to be a powerful analgesic, ~200 times the potency of morphine.[1]

Several total syntheses have been devised due to the relative scarcity of epibatidine in nature.[2]

Contents

Structure

It has been attempted previously to breed these frogs in a domesticated environment so that the alkaloid can be extracted. Interestingly, it was documented that although it was possible to breed these frogs artificially, they did not produce isolable amounts of the desired alkaloid.

Since epibatidine is extremely potent, only traces of this alkaloid are present on the skins of this breed of frog.

Presumably the frog produces this poison for self-defense purposes, particularly in the face of adversity from larger predators.

Coupled to the low concentration (traces) of epibatidine in the skins of these frogs, the frogs themselves are an endangered species.

The above two considerations frustrated attempts to discover the chemical structure of this exotic alkaloid and the project had to be shelved until more sensitive analytical techniques could facilitate in this compounds identification.

It was not until the development of the now established and sensitive technique of NMR in the 1990s that the structure of epibatidine could finally be ascertained with any degree of accuracy.[3]

Subsequent chemical syntheses of epibatidine also agree with the structure obtained from the natural sources.

Medicinal Application

At first it was suspected that epibatidine might be opioidergic although application of the narcotic antagonist naloxone failed to either block or reverse its antinociceptive effects. Subsequently it was discovered that the compound is instead an agonist at nicotinic acetylcholine receptors since mecamylamine was able to block the actions of this drug. In this regard, the compound has a completely novel mechanism of action at blocking nociceptive stimuli.[3]

Epibatidine is too toxic to use in clinical practice. In part, this is due to the fact that in addition to being an agonist at central nicotinic receptors, epibatidine is also believed to block neuromuscular junctions resulting in respiratory paralysis and death.[3]

It is rumored that Native Americans used to coat the tips of their arrows in the toxins secreted by the skins of these exotically colored frogs.

It is precisely because epibatidine is so insidiously lethal that it such a highly respected weapon in the chemical warfare department.

However, it is far too toxic to be used in the clinic. Indeed, sensitization to epibatidine occurs with repeat dosing, which might come as a surprise if it was expected that tolerance to its lethality occurs upon sustained exposure.

Nonetheless, this novel alkaloid served as an exciting lead in the search for novel analgesics.[3][4]

The aim of the drug design process is to dissociate the toxicity of this alkaloid from its antinociceptive properties which are hoped to provide a novel analgesic drug free from the dependence liability of classical narcotic analgesics acting on opiate receptors.

The study of nicotinic agonists is unpopular because of the link with smoking (tobacco leaves obviously contain nicotine). Nonetheless reviews in this area continue to be produced for the interested reader.[5]

Chemistry

Whereas popular drugs such as phenyltropane are semisynthetic, most of the designer epibatidine analogs so far have been totally synthetic.

The azabicyclic part of BZ for example has been used to make novel nicotinic agonists.

It is too early at this stage to for any of the new designer compounds to have been fully characterized yet.

Pharmacology

It has already been said numerous times (vide supra) that epibatidine is an agonist at nicotinic acetylcholine receptors.

Additionally, it was also stated that epibatidine causes respiratory paralysis because of its auxiliary actions at neuromuscular junctions.

To reiterate, the drug design process has attempted to create a relatively large number of analogs so that a SAR profile can be assembled.

It is wanted to retain the medically useful properties of epibatidine, but also to dispense with its deleterious actions.

In order to even make sense of what the 'beneficial' properties of epibatidine even are, it is first necessary to have some understanding of the nicotinic receptor subtypes.

Epibatidine is a potent agonist at both the α4β2 and the α3β4 sub-types of nicotinic receptor in particular.[1]

Bear in mind that epibatidine is relatively nonselective and is probably a strong agonist at most CNS nAChRs.

Additionally, agonists at the α7 subunit are expected to have medicinal properties.[6]

Clearly selective agonists are needed to ascertain the exact physiological role of each of these receptors.

More research is needed in this area before any of this can be documented.

Analogues

Of the tested epibatidine derivatives, Abbott Labs' ABT-594 (Tebanicline) is the most promising reported to date. ABT-594 was discovered to be 50 times more potent than morphine, yet on animal tests, no paralysis or depression of muscle action was observed. It completed Phase II clinical trials in Europe,[7] but while it showed clinical efficacy for treating neuropathic pain in humans it was dropped from further development due to unacceptable incidence of gastrointestinal side effects.[8] Further research in this area is ongoing.[9]

Epiboxidine is another one of the relatively well respected epibatidine analogs.

Epiboxidine is 1 tenth the potency of epibatidine but also said to be a lot less toxic.

Interestingly, epiboxidine is still regarded as too toxic for medicinal application, and its effects on man are undocumented.

References

  1. ^ a b Epibatidine - A review by Matthew J. Dowd
  2. ^ Olivo, Horacio F.; Hemenway, Michael S. Recent syntheses of epibatidine. A review. Organic Preparations and Procedures International (2002), 34(1), 1-26.
  3. ^ a b c d Decker, MW; Rueter; Bitner (2004). "Nicotinic acetylcholine receptor agonists: a potential new class of analgesics". Current topics in medicinal chemistry 4 (3): 369–84. doi:10.2174/1568026043451447. PMID 14754452.   edit
  4. ^ Carroll, F. (2004). "Epibatidine structure-activity relationships". Bioorganic & medicinal chemistry letters 14 (8): 1889–1896. doi:10.1016/j.bmcl.2004.02.007. PMID 15050621.   edit
  5. ^ Romanelli, M.; Gratteri, P.; Guandalini, L.; Martini, E.; Bonaccini, C.; Gualtieri, F. (2007). "Central nicotinic receptors: structure, function, ligands, and therapeutic potential". ChemMedChem 2 (6): 746–767. doi:10.1002/cmdc.200600207. PMID 17295372.   edit
  6. ^ Lightfoot AP, Kew JN, Skidmore J. Alpha7 nicotinic acetylcholine receptor agonists and positive allosteric modulators. Prog Med Chem. 2008;46:131-71. PMID 18381125
  7. ^ The New Morphine
  8. ^ Livett, B.; Sandall, D.; Keays, D.; Down, J.; Gayler, K.; Satkunanathan, N.; Khalil, Z. (2006). "Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor". Toxicon : official journal of the International Society on Toxinology 48 (7): 810–829. doi:10.1016/j.toxicon.2006.07.023. PMID 16979678.   edit
  9. ^ Bunnelle, W.; Daanen, J.; Ryther, K.; Schrimpf, M.; Dart, M.; Gelain, A.; Meyer, M.; Frost, J. et al. (2007). "Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors". Journal of medicinal chemistry 50 (15): 3627–3644. doi:10.1021/jm070018l. PMID 17585748.   edit

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