Epibatidine: Difference between revisions

Epibatidine
Identifiers
	IUPAC name (1R,2R,4S)-(+)-6-(6-Chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane;
CAS Number	140111-52-0 ;
PubChem CID	1204;
DrugBank	DB07720 ;
ChemSpider	10399316 ;
UNII	M6K314F1XX;
KEGG	C11690 ;
ChEBI	CHEBI:4803;
ChEMBL	ChEMBL298826 ;
ECHA InfoCard	100.162.281
Chemical and physical data
Formula	C11H13ClN2
Molar mass	208.69 g·mol−1
3D model (JSmol)	Interactive image;
Density	1.2 ± 0.1 g/cm3 g/cm3
	SMILES ClC1=CC=C([C@@H]2C[C@]3([H])CC[C@@]2([H])N3)C=N1;
	InChI InChI=1S/C11H13ClN2/c12-11-4-1-7(6-13-11)9-5-8-2-3-10(9)14-8/h1,4,6,8-10,14H,2-3,5H2/t8-,9+,10+/m0/s1 ; Key:NLPRAJRHRHZCQQ-IVZWLZJFSA-N ;
	(what is this?) (verify)

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Latest revision as of 12:18, 31 October 2024

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus.^[1] It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine occurs naturally remains controversial due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.^[2]

Epibatidine is toxic. Its toxicity stems from its ability to interact with nicotinic and muscarinic acetylcholine receptors. These receptors are involved in the transmission of painful sensations, and in movement, among other functions. Epibatidine then 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. However, because of its unacceptable therapeutic index, it is no longer being researched for potential therapeutic uses.^[3]

History

Epibatidine was discovered by John W. Daly in 1974. It was isolated from the skin of Epipedobates anthonyi frogs collected by Daly and colleague, 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) effects in mice that resembled those of an opioid.^[2] Despite 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]

The structure of epibatidine was elucidated in 1992, an effort hindered by E. anthonyi gaining IUCN protected status in 1984.^[5] Furthermore, these frogs do not produce the toxin when bred and reared in captivity, because they do not synthesize epibatidine themselves. Like other poison dart frogs, they instead obtain it through their diet and then sequester it on their skin. Likely dietary sources are beetles, ants, mites, and flies.^[6] Daly and Charles noticed that epibatidine was produced from their diet due to their return trip to Ecuador in 1976 when they found that at one site, none of the frogs present produced alkaloids, such as epibatidine; they discovered that only the frogs at certain sites with the dietary means allowed these frogs to produce epibatidine.^[7] Overcoming the difficulties, the structure was eventually determined, and the first synthesis of epibatidine was completed in 1993. Many other synthesis methods have been developed since.^[5]

Because of its analgesic effect, there was intense interest in epibatidine's use as a drug, because it was found not to be an opioid.^[2] This meant that it could potentially be used without fear of addiction. However, it was soon found that it cannot be used in humans because the dose resulting in toxic symptoms is too low for it to be safe.^[8]

Synthesis

Several total synthesis routes have been devised due to the relative scarcity of epibatidine in nature.^[9]

After the discovery of the structure of epibatidine, more than fifty ways to synthesize it in the laboratory have been devised. In the first reported example, a nine-step procedure produces the substance as a racemate (in contrast, the naturally occurring compound is the (+)-enantiomer; the (−)-enantiomer does not occur naturally). 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%.^[10]^[11]^[12]

An enantioselective synthesis reported by E J Corey starting from chloronicotinaldehyde is outlined below:

In addition to Corey's method, other notable methods include those of Broka,^[13] Huang and Shen,^[14] and Clayton and Regan.^[11]

Synthetic analogs

A number of approaches to discovering structural analogs of epibatine that maintain analgesics effects, but without the toxicity, have been attempted.^[15] For example, Abbott Laboratories has produced derivatives of epibatidine including tebanicline (ABT-594).^[16] Tebanicline retains analgesic properties while avoiding paralysis by still binding to receptors that control pain perception and having a low affinity for muscle-type nicotinic acetylcholine receptors (nAChR) reducing its paralysis effect.^[17] Other epibatidine analogs include ABT-418, epiboxidine, and their derivatives.^[15]^[18]^[19]^[20]^[21] A synthesis of epibatidine, utilizing a microbial hydroxylation of an unactivated carbon in a 7-azanorbornane was published in 1999.^[22]

Chemical structure

Epibatidine is a piperidine pyridine with a structure similar to that of nicotine.^[23] It is a hygroscopic oily substance which is a base.

Biological effects

Mechanism of action

Epibatidine has two mechanisms of action: it can bind to either nicotinic acetylcholine receptors (nAChR) or muscarinic acetylcholine receptors (mAChR). Specifically, the analgesic property of epibatidine is believed to take place by its binding to the α4/β2 subtype of nicotinic receptors. Epibatidine also binds to the α3/β4 subtype and to a much lesser extent α7 receptors (affinity 300-fold less than for α4/β2)^[24] The rank order of affinities for the muscle nicotinic receptors is αε > αγ > αδ.^[25]

Nicotinic acetylcholine receptors are found in the post-synaptic membranes of nerve cells. These receptors are an example of ion gated channels where binding by a ligand causes a conformational change allowing ions to cross the membrane into the cell.^[26] They propagate neurotransmission in the central and peripheral nervous system. When neurotransmitters bind to these receptors, ion channels open, allowing Na⁺ and Ca²⁺ ions to move across the membrane. This depolarizes the post-synaptic membrane, inducing an action potential that propagates the signal. This signal will ultimately induce release of dopamine and norepinephrine, resulting in an antinociceptive effect on the organism. The usual neurotransmitter for nAChR is acetylcholine. However, other substances (such as epibatidine and nicotine) are also able to bind to the receptor and induce a similar, if not identical, response. Epibatidine has an extremely high affinity for nAChRs, depending on the receptor subtype, from 0.05 nM at the α4β2 subtype to 22 nM at the α7 subtype. Affinity as well as efficacy (and thus also potency) are much higher than for nicotine.^[10]

The paralytic property of epibatidine takes place after its binding to muscle-type nicotinic receptors.

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.

Both (+)- and (-)-enantiomers of epibatidine are biologically active, and both have similar binding affinities to nAChRs^[10] Only the (+)-enantiomer does not induce tolerance. While this may be a potential therapeutic advantage over morphine, epibatidine has not entered clinical trials because even very small doses are lethal to rodents.^[27]

Symptoms

Epibatidine has several toxic consequences. Empirically proven effects include splanchnic sympathetic nerve discharge and increased arterial pressure.^[23] The nerve discharge effects can cause antinociception partially mediated by agonism of central nicotinic acetylcholine receptors at low doses of epibatidine; 5 μg/kg.^[28] 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 and 13.98 μg/kg.^[29] This makes epibatidine somewhat more toxic than dioxin (with an average LD₅₀ of 22.8 μg/kg).^{[citation needed]} Due to the small difference between its toxic concentration and antinociceptive concentration, its therapeutic uses are very limited.

In research on mice, administration of doses greater than 5 μg/kg of epibatidine caused a dose-dependent paralyzing effect on the organism. With doses over 5 μg/kg, 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

Epibatidine most effectively enters the body through injection.^[30] In vitro studies seem to suggest that epibatidine is hardly, if at all, metabolized in the human body.^[31]

Also there is currently little information on the path of clearance from the body. Maximum concentration in the brain is reached at about 30 minutes after entering the body.^[10]

Potential medical uses

Epibatidine has a high analgesic potency, as stated above. Studies show it has a potency at least 200 times that of morphine.^[10] As the compound was not addictive nor did it cause habituation,^{[citation needed]}, it was initially thought to be very promising to replace morphine as a painkiller. However, the therapeutic concentration is very close to the toxic concentration. This means that even at a therapeutic dose (5 μg/kg^[28]), some epibatidine might bind to the muscarinic acetylcholine receptors and cause adverse effects, such as hypertension, bradycardia and muscular paresis.^[23]

Compared to the gold standard in pain management, morphine, epibatidine needed only 2.5 μg/kg (11.98 nmol/kg) to initiate a pain-relieving effect whilst the same effect required approximately 10 mg/kg (35.05 μmol/kg) of morphine (approx. 2,900 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.^[12]

Antidote

The antidote to epibatidine is mecamylamine,^[32] a nicotinic acetylcholine receptor antagonist that is non-selective and non-competitive.^[33] Both the (+) and the (-) enantiomers of mecamylamine were seen to be efficient and both have the same affinity for nicotinic acetylcholine receptors.^[34]

References

^ Fitch RW, Spande TF, Garraffo HM, Yeh HJ, Daly JW (March 2010). "Phantasmidine: an epibatidine congener from the ecuadorian poison frog Epipedobates anthonyi". Journal of Natural Products. 73 (3): 331–337. doi:10.1021/np900727e. PMC 2866194. PMID 20337496.
^ ^a ^b ^c Garraffo HM, Spande TF, Williams M (April 2009). "Epibatidine: from frog alkaloid to analgesic clinical candidates: a testimonial to" true grit"!" (PDF). Heterocycles. 79 (1): 207–217. doi:10.3987/REV-08-SR(D)5.
^ Schwarcz J (2012). The Right Chemistry. Random House.
^ Maxon J, Whittaker K (March 2009). "Epipedobates anthonyi". Berkeley, CA, USA: University of California. Retrieved 2015-05-06.
^ ^a ^b ^c Daly JW, Garraffo HM, Spande TF, Decker MW, Sullivan JP, Williams M (April 2000). "Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics". Natural Product Reports. 17 (2): 131–135. doi:10.1039/a900728h. PMID 10821107.
^ Lasley EN (December 1999). "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". BioScience. 45 (12). Oxford Journals: 945–950. doi:10.1525/bisi.1999.49.12.945.
^ Daly JW, Garraffo HM, Spande TF, Decker MW, Sullivan JP, Williams M (April 2000). "Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics". Natural Product Reports. 17 (2): 131–135. doi:10.1039/A900728H. PMID 10821107.
^ Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, et al. (May 1998). "ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 777–786. PMID 9580626.
^ Olivo HF, Hemenway MS (2002). "Recent syntheses of epibatidine. A review". Organic Preparations and Procedures International. 34 (1): 1–26. doi:10.1080/00304940209355744. S2CID 98696766.
^ ^a ^b ^c ^d ^e Traynor JR (July 1998). "Epibatidine and pain". British Journal of Anaesthesia. 81 (1): 69–76. doi:10.1093/bja/81.1.69. PMID 9771274.
^ ^a ^b Clayton SC, Regan AC (1993). "A total synthesis of (±)-epibatidine". Tetrahedron Letters. 34 (46): 7493–7496. doi:10.1016/S0040-4039(00)60162-4.
^ ^a ^b Broka CA (1994). "Synthetic approaches to epibatidine". Medicinal Chemistry Research. 4 (7): 449–460.
^ Broka CA (1993). "Total synthesis of epibatidine". Tetrahedron Lett. 34 (20): 3251–3254. doi:10.1016/s0040-4039(00)73674-4.
^ Huang DF, Shen TY (1993). "A versatile total synthesis of epibatidine and analogs". Tetrahedron Lett. 34 (28): 4477–4480. doi:10.1016/0040-4039(93)88063-o.
^ ^a ^b Dowd MJ. "Epibatidine". Department of Medicinal Chemistry. Virginia Commonwealth University. Archived from the original on December 5, 2010.
^ "Deriving a non-opiate painkiller [ABT-594] from Epipedobates tricolor". Mongabay.com. Retrieved 2014-03-12.
^ "Epibatidine". School of Chemistry. University of Bristol. Retrieved 2021-11-12.
^ Rizzi L, Dallanoce C, Matera C, Magrone P, Pucci L, Gotti C, et al. (August 2008). "Epiboxidine and novel-related analogues: a convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes". Bioorganic & Medicinal Chemistry Letters. 18 (16): 4651–4654. doi:10.1016/j.bmcl.2008.07.016. hdl:2434/59291. PMID 18644719.
^ Dallanoce C, Matera C, De Amici M, Rizzi L, Pucci L, Gotti C, et al. (July 2012). "The enantiomers of epiboxidine and of two related analogs: synthesis and estimation of their binding affinity at α4β2 and α7 neuronal nicotinic acetylcholine receptors". Chirality. 24 (7): 543–551. doi:10.1002/chir.22052. PMID 22566097.
^ Dallanoce C, Matera C, Pucci L, Gotti C, Clementi F, Amici MD, Micheli CD (January 2012). "Synthesis and binding affinity at α4β2 and α7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7-azabicyclo[2.2.1]hept-2-ene ring system". Bioorganic & Medicinal Chemistry Letters. 22 (2): 829–832. doi:10.1016/j.bmcl.2011.12.052. PMID 22222032.
^ Dallanoce C, Magrone P, Matera C, Lo Presti L, De Amici M, Riganti L, et al. (December 2010). "Synthesis of novel chiral Δ2-isoxazoline derivatives related to ABT-418 and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes". European Journal of Medicinal Chemistry. 45 (12): 5594–5601. doi:10.1016/j.ejmech.2010.09.009. PMID 20932609.
^ Olivo HF, Hemenway MS (November 1999). "Total Synthesis of (+/-)-Epibatidine Using a Biocatalytic Approach". The Journal of Organic Chemistry. 64 (24): 8968–8969. doi:10.1021/jo991141q. PMID 11674810.
^ ^a ^b ^c Fisher M, Huangfu D, Shen TY, Guyenet PG (August 1994). "Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent". The Journal of Pharmacology and Experimental Therapeutics. 270 (2): 702–707. PMID 8071862.
^ Traynor JR (July 1998). "Epibatidine and pain". British Journal of Anaesthesia. 81 (1): 69–76. doi:10.1093/bja/81.1.69. PMID 9771274.
^ Prince RJ, Sine SM (April 1998). "Epibatidine binds with unique site and state selectivity to muscle nicotinic acetylcholine receptors". The Journal of Biological Chemistry. 273 (14): 7843–7849. doi:10.1074/jbc.273.14.7843. PMID 9525877.
^ Hogg RC, Raggenbass M, Bertrand D (2003). "Nicotinic acetylcholine receptors: from structure to brain function". Reviews of Physiology, Biochemistry and Pharmacology. 147: 1–46. doi:10.1007/s10254-003-0005-1. ISBN 978-3-540-01365-5. PMID 12783266.
^ Olena A (September 21, 2017). "How Poison Frogs Avoid Poisoning Themselves". The Scientist.
^ ^a ^b Badio B, Daly JW (April 1994). "Epibatidine, a potent analgetic and nicotinic agonist". Molecular Pharmacology. 45 (4): 563–9. PMID 8183234.
^ Sihver W, Långström B, Nordberg A (2002). "Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain". Acta Neurologica Scandinavica. Supplementum. 176: 27–33. doi:10.1034/j.1600-0404.2000.00304.x. PMID 11261802. S2CID 23541883.
^ Sullivan JP, Bannon AW (1996). "Epibatidine: Pharmacological Properties of a Novel Nicotinic Acetylcholine Receptor Agonist and Analgesic Agent". CNS Drug Reviews. 2 (1): 21–39. doi:10.1111/j.1527-3458.1996.tb00288.x.
^ Watt AP, Hitzel L, Morrison D, Locker KL (October 2000). "Determination of the in vitro metabolism of (+)- and (-)-epibatidine". Journal of Chromatography A. 896 (1–2): 229–38. doi:10.1016/s0021-9673(00)00597-5. PMID 11093658.
^ Damaj MI, Creasy KR, Grove AD, Rosecrans JA, Martin BR (November 1994). "Pharmacological effects of epibatidine optical enantiomers". Brain Research. 664 (1–2): 34–40. doi:10.1016/0006-8993(94)91950-x. PMID 7895043. S2CID 46489298.
^ Bacher I, Wu B, Shytle DR, George TP (November 2009). "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. PMID 19874251. S2CID 25690407.
^ Nickell JR, Grinevich VP, Siripurapu KB, Smith AM, Dwoskin LP (July 2013). "Potential therapeutic uses of mecamylamine and its stereoisomers". Pharmacology, Biochemistry, and Behavior. 108: 28–43. doi:10.1016/j.pbb.2013.04.005. PMC 3690754. PMID 23603417.

External links

Epibatidine at chemsoc.org

[1] Fitch RW, Spande TF, Garraffo HM, Yeh HJ, Daly JW (March 2010). "Phantasmidine: an epibatidine congener from the ecuadorian poison frog Epipedobates anthonyi". Journal of Natural Products. 73 (3): 331–337. doi:10.1021/np900727e. PMC 2866194. PMID 20337496.

[H.M._Garraffo_(2009)-2] Garraffo HM, Spande TF, Williams M (April 2009). "Epibatidine: from frog alkaloid to analgesic clinical candidates: a testimonial to" true grit"!" (PDF). Heterocycles. 79 (1): 207–217. doi:10.3987/REV-08-SR(D)5.

[Schwarcz,_Joe-3] Schwarcz J (2012). The Right Chemistry. Random House.

[Epipedobates_anthonyi-4] Maxon J, Whittaker K (March 2009). "Epipedobates anthonyi". Berkeley, CA, USA: University of California. Retrieved 2015-05-06.

[J.W._Daly_(2000)-5] Daly JW, Garraffo HM, Spande TF, Decker MW, Sullivan JP, Williams M (April 2000). "Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics". Natural Product Reports. 17 (2): 131–135. doi:10.1039/a900728h. PMID 10821107.

[E.N._Lasley_(1999)-6] Lasley EN (December 1999). "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". BioScience. 45 (12). Oxford Journals: 945–950. doi:10.1525/bisi.1999.49.12.945.

[7] Daly JW, Garraffo HM, Spande TF, Decker MW, Sullivan JP, Williams M (April 2000). "Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics". Natural Product Reports. 17 (2): 131–135. doi:10.1039/A900728H. PMID 10821107.

[Donnelly-Roberts-8] Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, et al. (May 1998). "ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 777–786. PMID 9580626.

[9] Olivo HF, Hemenway MS (2002). "Recent syntheses of epibatidine. A review". Organic Preparations and Procedures International. 34 (1): 1–26. doi:10.1080/00304940209355744. S2CID 98696766.

[Traynor-10] Traynor JR (July 1998). "Epibatidine and pain". British Journal of Anaesthesia. 81 (1): 69–76. doi:10.1093/bja/81.1.69. PMID 9771274.

[car-11] Clayton SC, Regan AC (1993). "A total synthesis of (±)-epibatidine". Tetrahedron Letters. 34 (46): 7493–7496. doi:10.1016/S0040-4039(00)60162-4.

[Broka-12] Broka CA (1994). "Synthetic approaches to epibatidine". Medicinal Chemistry Research. 4 (7): 449–460.

[13] Broka CA (1993). "Total synthesis of epibatidine". Tetrahedron Lett. 34 (20): 3251–3254. doi:10.1016/s0040-4039(00)73674-4.

[14] Huang DF, Shen TY (1993). "A versatile total synthesis of epibatidine and analogs". Tetrahedron Lett. 34 (28): 4477–4480. doi:10.1016/0040-4039(93)88063-o.

[Dowd-15] Dowd MJ. "Epibatidine". Department of Medicinal Chemistry. Virginia Commonwealth University. Archived from the original on December 5, 2010.

[16] "Deriving a non-opiate painkiller [ABT-594] from Epipedobates tricolor". Mongabay.com. Retrieved 2014-03-12.

[17] "Epibatidine". School of Chemistry. University of Bristol. Retrieved 2021-11-12.

[18] Rizzi L, Dallanoce C, Matera C, Magrone P, Pucci L, Gotti C, et al. (August 2008). "Epiboxidine and novel-related analogues: a convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes". Bioorganic & Medicinal Chemistry Letters. 18 (16): 4651–4654. doi:10.1016/j.bmcl.2008.07.016. hdl:2434/59291. PMID 18644719.

[19] Dallanoce C, Matera C, De Amici M, Rizzi L, Pucci L, Gotti C, et al. (July 2012). "The enantiomers of epiboxidine and of two related analogs: synthesis and estimation of their binding affinity at α4β2 and α7 neuronal nicotinic acetylcholine receptors". Chirality. 24 (7): 543–551. doi:10.1002/chir.22052. PMID 22566097.

[20] Dallanoce C, Matera C, Pucci L, Gotti C, Clementi F, Amici MD, Micheli CD (January 2012). "Synthesis and binding affinity at α4β2 and α7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7-azabicyclo[2.2.1]hept-2-ene ring system". Bioorganic & Medicinal Chemistry Letters. 22 (2): 829–832. doi:10.1016/j.bmcl.2011.12.052. PMID 22222032.

[21] Dallanoce C, Magrone P, Matera C, Lo Presti L, De Amici M, Riganti L, et al. (December 2010). "Synthesis of novel chiral Δ2-isoxazoline derivatives related to ABT-418 and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes". European Journal of Medicinal Chemistry. 45 (12): 5594–5601. doi:10.1016/j.ejmech.2010.09.009. PMID 20932609.

[22] Olivo HF, Hemenway MS (November 1999). "Total Synthesis of (+/-)-Epibatidine Using a Biocatalytic Approach". The Journal of Organic Chemistry. 64 (24): 8968–8969. doi:10.1021/jo991141q. PMID 11674810.

[M._Fisher-23] Fisher M, Huangfu D, Shen TY, Guyenet PG (August 1994). "Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent". The Journal of Pharmacology and Experimental Therapeutics. 270 (2): 702–707. PMID 8071862.

[24] Traynor JR (July 1998). "Epibatidine and pain". British Journal of Anaesthesia. 81 (1): 69–76. doi:10.1093/bja/81.1.69. PMID 9771274.

[25] Prince RJ, Sine SM (April 1998). "Epibatidine binds with unique site and state selectivity to muscle nicotinic acetylcholine receptors". The Journal of Biological Chemistry. 273 (14): 7843–7849. doi:10.1074/jbc.273.14.7843. PMID 9525877.

[26] Hogg RC, Raggenbass M, Bertrand D (2003). "Nicotinic acetylcholine receptors: from structure to brain function". Reviews of Physiology, Biochemistry and Pharmacology. 147: 1–46. doi:10.1007/s10254-003-0005-1. ISBN 978-3-540-01365-5. PMID 12783266.

[27] Olena A (September 21, 2017). "How Poison Frogs Avoid Poisoning Themselves". The Scientist.

[Daly-28] Badio B, Daly JW (April 1994). "Epibatidine, a potent analgetic and nicotinic agonist". Molecular Pharmacology. 45 (4): 563–9. PMID 8183234.

[29] Sihver W, Långström B, Nordberg A (2002). "Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain". Acta Neurologica Scandinavica. Supplementum. 176: 27–33. doi:10.1034/j.1600-0404.2000.00304.x. PMID 11261802. S2CID 23541883.

[Sullivan-30] Sullivan JP, Bannon AW (1996). "Epibatidine: Pharmacological Properties of a Novel Nicotinic Acetylcholine Receptor Agonist and Analgesic Agent". CNS Drug Reviews. 2 (1): 21–39. doi:10.1111/j.1527-3458.1996.tb00288.x.

[pmid11093658-31] Watt AP, Hitzel L, Morrison D, Locker KL (October 2000). "Determination of the in vitro metabolism of (+)- and (-)-epibatidine". Journal of Chromatography A. 896 (1–2): 229–38. doi:10.1016/s0021-9673(00)00597-5. PMID 11093658.

[Damaj-32] Damaj MI, Creasy KR, Grove AD, Rosecrans JA, Martin BR (November 1994). "Pharmacological effects of epibatidine optical enantiomers". Brain Research. 664 (1–2): 34–40. doi:10.1016/0006-8993(94)91950-x. PMID 7895043. S2CID 46489298.

[Bacher-33] Bacher I, Wu B, Shytle DR, George TP (November 2009). "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. PMID 19874251. S2CID 25690407.

[34] Nickell JR, Grinevich VP, Siripurapu KB, Smith AM, Dwoskin LP (July 2013). "Potential therapeutic uses of mecamylamine and its stereoisomers". Pharmacology, Biochemistry, and Behavior. 108: 28–43. doi:10.1016/j.pbb.2013.04.005. PMC 3690754. PMID 23603417.

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+{{Short description|Toxic chemical from some poison dart frogs}}
-{{distinguish|Eptifibatide}}
+{{Distinguish|Eptifibatide}}
-{{Drugbox
+{{Infobox drug
-| Verifiedfields = changed
-| Watchedfields = changed
+| Verifiedfields     = changed
+| Watchedfields      = changed
-| verifiedrevid = 443729000
+| verifiedrevid      = 443729000
-| IUPAC_name = (1''R'',2''R'',4''S'')-(+)-6-(6-Chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane
+| IUPAC_name         = (1''R'',2''R'',4''S'')-(+)-6-(6-Chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane
-| image = (+)-Epibatidine Structural Formulae V.1.svg
+| image              = Epibatidine structure.svg
+| image2             = Epibatidine molecule ball.png
-<!--Clinical data-->
-| tradename =
+<!--Clinical data-->| tradename          =
 | pregnancy_category =
-| legal_status =
+| legal_status       =
-| routes_of_administration =
+| routes_of_administration = <!--Pharmacokinetic data-->
+| bioavailability    =
+| protein_bound      =
-<!--Pharmacokinetic data-->
+| metabolism         =
-| bioavailability =
+| elimination_half-life =
-| protein_bound =
+| excretion          = <!--Identifiers-->
-| metabolism =
+| CAS_number_Ref     = {{cascite|correct|??}}
-| elimination_half-life =
+| CAS_number         = 140111-52-0
-| excretion =
+| UNII_Ref           = {{fdacite|correct|FDA}}
+| UNII               = M6K314F1XX
-<!--Identifiers-->
+| ATC_prefix         =
-| CAS_number_Ref = {{cascite|correct|??}}
+| ATC_suffix         =
-| CAS_number = 140111-52-0
+| PubChem            = 1204
-| UNII_Ref = {{fdacite|correct|FDA}}
+| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
-| UNII = M6K314F1XX
+| DrugBank           = DB07720
-| ATC_prefix =
+| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
-| ATC_suffix =
+| ChemSpiderID       = 10399316
-| PubChem = 11031065
+| ChEBI              = 4803
-| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
+| ChEMBL_Ref         = {{ebicite|correct|EBI}}
-| DrugBank = DB07720
+| ChEMBL             = 298826
-| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
+| KEGG_Ref           = {{keggcite|changed|kegg}}
-| ChemSpiderID = 10399316
+| KEGG               = C11690
-| ChEBI = 4803
-| ChEMBL_Ref = {{ebicite|correct|EBI}}
-| ChEMBL = 298826
-| KEGG_Ref = {{keggcite|changed|kegg}}
-| KEGG = C11690
 <!--Chemical data-->
-| C=11 | H=13 | Cl=1 | N=2
+| C                  = 11
+| H                  = 13
-| smiles = ClC1=CC=C([C@@H]2C[C@]3([H])CC[C@@]2([H])N3)C=N1
+| Cl                 = 1
-| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
+| N                  = 2
-| StdInChI = 1S/C11H13ClN2/c12-11-4-1-7(6-13-11)9-5-8-2-3-10(9)14-8/h1,4,6,8-10,14H,2-3,5H2/t8-,9+,10+/m0/s1
+| smiles             = ClC1=CC=C([C@@H]2C[C@]3([H])CC[C@@]2([H])N3)C=N1
-| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
+| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
-| StdInChIKey = NLPRAJRHRHZCQQ-IVZWLZJFSA-N
+| StdInChI           = 1S/C11H13ClN2/c12-11-4-1-7(6-13-11)9-5-8-2-3-10(9)14-8/h1,4,6,8-10,14H,2-3,5H2/t8-,9+,10+/m0/s1
+| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
+| density            = 1.2 ± 0.1 g/cm<sup>3</sup>
+| StdInChIKey        = NLPRAJRHRHZCQQ-IVZWLZJFSA-N
 }}
-'''Epibatidine''' is a chlorinated [[alkaloid]] that is secreted by the [[Ecuador]]an frog ''[[Epipedobates anthonyi]]''.<ref>{{Cite journal | doi = 10.1021/np900727e| pmid = 20337496| title = Phantasmidine: An Epibatidine Congener from the Ecuadorian Poison Frog ''Epipedobates'' anthonyi⊥| journal = Journal of Natural Products| volume = 73| issue = 3| pages = 331–7| year = 2010| last1 = Fitch | first1 = R. W. | last2 = Spande | first2 = T. F. | last3 = Garraffo | first3 = H. M. | last4 = Yeh | first4 = H. J. C. | last5 = Daly | first5 = J. W. | pmc=2866194}}</ref>  It was discovered by [[John W. Daly]] in 1974, but its structure was not fully elucidated until 1992.  Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly.  By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination.  Samples from other batches of the same species of frog failed to yield epibatidine.
+'''Epibatidine''' is a chlorinated [[alkaloid]] that is secreted by the [[Ecuador]]an frog ''[[Epipedobates anthonyi]]'' and [[poison dart frog]]s from the ''[[Ameerega]]'' genus.<ref>{{cite journal | vauthors = Fitch RW, Spande TF, Garraffo HM, Yeh HJ, Daly JW | title = Phantasmidine: an epibatidine congener from the ecuadorian poison frog Epipedobates anthonyi | journal = Journal of Natural Products | volume = 73 | issue = 3 | pages = 331–337 | date = March 2010 | pmid = 20337496 | pmc = 2866194 | doi = 10.1021/np900727e }}</ref>  It was discovered by [[John W. Daly]] in 1974, but its structure was not fully elucidated until 1992.  Whether epibatidine occurs naturally remains controversial due to challenges in conclusively identifying the compound from the limited samples collected by Daly.  By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination.  Samples from other batches of the same species of frog failed to yield epibatidine.<ref name="H.M. Garraffo (2009)">{{cite journal | vauthors = Garraffo HM, Spande TF, Williams M | title = Epibatidine: from frog alkaloid to analgesic clinical candidates: a testimonial to" true grit"!. | journal = Heterocycles | date = April 2009 | volume = 79 | issue = 1 | pages = 207–217 | doi = 10.3987/REV-08-SR(D)5 | url = http://www.chm.bris.ac.uk/sillymolecules/epibatidine.pdf }}</ref>
-<ref name="H.M. Garraffo (2009)">{{cite web|url=http://www.chm.bris.ac.uk/sillymolecules/epibatidine.pdf |title=Epibatidine: From Frog Alkaloid to Analgesic Clinical Candidates. A Testimonial to "True Grit"! |volume=79 |publisher=Heterocycles |issue=1 |pages=207–217 |accessdate=2015-05-06}}</ref>
-Epibatidine is toxic.  Its toxicity stems from its ability to interact with [[nicotinic acetylcholine receptor|nicotinic]] and [[muscarinic acetylcholine receptor]]s.  These receptors are involved in the transmission of painful sensations, and in movement, among other functions.  Epibatidine then 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.  However, because of its unacceptable [[therapeutic index]], it is no longer being researched for potential therapeutic uses.<ref name="Schwarcz, Joe">{{cite book |last1=Schwarcz |first1=Joe |title=The Right Chemistry |publisher=Random House |year=2012}}</ref>
+Epibatidine is toxic.  Its toxicity stems from its ability to interact with [[nicotinic acetylcholine receptor|nicotinic]] and [[muscarinic acetylcholine receptor]]s.  These receptors are involved in the transmission of painful sensations, and in movement, among other functions.  Epibatidine then 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.  However, because of its unacceptable [[therapeutic index]], it is no longer being researched for potential therapeutic uses.<ref name="Schwarcz, Joe">{{cite book | vauthors = Schwarcz J |title=The Right Chemistry |publisher=Random House |year=2012}}</ref>
 ==History==
-Epibatidine was discovered by [[John W. Daly]] in 1974. It was isolated from the skin of ''Epipdobates anthonyi'' frogs collected by Daly and colleague, 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) effects in mice that resembled those of an [[opioid]].<ref name="H.M. Garraffo (2009)"/> Despite its common name - Anthony's Poison Arrow frog - suggesting that it was used by natives when hunting,<ref name="Epipedobates anthonyi">{{cite web|url=http://amphibiaweb.org/cgi/amphib_query?where-genus=Epipedobates&where-species=anthonyi |title=''Epipedobates anthonyi'' |accessdate=2015-05-06}}</ref> 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.<ref name="J.W. Daly (2000)">{{cite journal |doi=10.1039/a900728h |title=Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics |author= Daly |author2= Garraffo |last-author-amp= yes |journal=  Natural Product Reports|volume=17 |issue=2 |pages=131–135 |year=2000 |url=https://zenodo.org/record/1229984 }}</ref>
+Epibatidine was discovered by [[John W. Daly]] in 1974. It was isolated from the skin of ''Epipedobates anthonyi'' frogs collected by Daly and colleague, 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) effects in mice that resembled those of an [[opioid]].<ref name="H.M. Garraffo (2009)"/> Despite its common name - Anthony's Poison Arrow frog - suggesting that it was used by natives when hunting,<ref name="Epipedobates anthonyi">{{cite web | vauthors =  Maxon J, Whittaker K | date = March 2009 | url=http://amphibiaweb.org/cgi/amphib_query?where-genus=Epipedobates&where-species=anthonyi |title=''Epipedobates anthonyi'' |access-date=2015-05-06 | publisher = University of California | location = Berkeley, CA, USA }}</ref> 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.<ref name="J.W. Daly (2000)">{{cite journal | vauthors = Daly JW, Garraffo HM, Spande TF, Decker MW, Sullivan JP, Williams M | title = Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics | journal = Natural Product Reports | volume = 17 | issue = 2 | pages = 131–135 | date = April 2000 | pmid = 10821107 | doi = 10.1039/a900728h | url = https://zenodo.org/record/1229984 | name-list-style = amp }}</ref>
 [[File:Epipedobates tricolor1.jpg|thumb|left|alt=A photo of a ''Epipedobates tricolor'' on a leaf|''Epipedobates tricolor'' on a leaf]]
-The structure of epibatidine was elucidated in 1992, an effort hindered by ''E. anthonyi'' gaining IUCN protected status in 1984.<ref name="J.W. Daly (2000)"/> Furthermore, these frogs do not produce the toxin when bred and reared in captivity, because they do not synthesize epibatidine themselves. Like other poison dart frogs, they instead obtain it through their diet and then sequester it on their skin. Likely dietary sources are beetles, ants, mites, and flies.<ref name="E.N. Lasley (1999)">{{cite journal|url=http://bioscience.oxfordjournals.org/content/49/12/945.full |title=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 |journal=BioScience |author=Elizabeth Norton Lasley |publisher=Oxford Journals |volume=45 |issue=12 |pages=945–950 |access-date=2015-05-06|doi=10.1525/bisi.1999.49.12.945 |date=December 1999 |doi-access=free }}</ref> Overcoming the difficulties, the structure was eventually determined, and the first synthesis of epibatidine was completed in 1993. Many other synthesis methods have been developed since.<ref name="J.W. Daly (2000)"/>
+The structure of epibatidine was elucidated in 1992, an effort hindered by ''E. anthonyi'' gaining [[International Union for Conservation of Nature|IUCN]] protected status in 1984.<ref name="J.W. Daly (2000)"/> Furthermore, these frogs do not produce the toxin when bred and reared in captivity, because they do not synthesize epibatidine themselves. Like other poison dart frogs, they instead obtain it through their diet and then sequester it on their skin. Likely dietary sources are beetles, ants, mites, and flies.<ref name="E.N. Lasley (1999)">{{cite journal|title=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 |journal=BioScience | vauthors = Lasley EN |publisher=Oxford Journals |volume=45 |issue=12 |pages=945–950 |doi=10.1525/bisi.1999.49.12.945 |date=December 1999 |doi-access=free }}</ref> Daly and Charles noticed that epibatidine was produced from their diet due to their return trip to Ecuador in 1976 when they found that at one site, none of the frogs present produced alkaloids, such as epibatidine; they discovered that only the frogs at certain sites with the dietary means allowed these frogs to produce epibatidine.<ref>{{cite journal | vauthors = Daly JW, Garraffo HM, Spande TF, Decker MW, Sullivan JP, Williams M | title = Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics | journal = Natural Product Reports | volume = 17 | issue = 2 | pages = 131–135 | date = April 2000 | pmid = 10821107 | doi = 10.1039/A900728H | url = https://zenodo.org/record/1229984 }}</ref> Overcoming the difficulties, the structure was eventually determined, and the first synthesis of epibatidine was completed in 1993. Many other synthesis methods have been developed since.<ref name="J.W. Daly (2000)"/>
-Because of its analgesic effect, there was intense interest in epibatidine's use as a drug, because it was found not to be an opioid.<ref name="H.M. Garraffo (2009)"/> This meant that it could potentially be used without fear of addiction. However, it was soon found that it cannot be used in humans because the dose resulting in toxic symptoms is too low for it to be safe.<ref name="Donnelly-Roberts">{{cite journal |title=ABT-594 [(R)-5-(2-Azetidinylmethoxy)-2-Chloropyridine]: A Novel, Orally Effective Analgesic Acting via Neuronal Nicotinic Acetylcholine Receptors: I. In Vitro Characterization |author=Diana L. Donnelly-Roberts |author2=Pamela S. Puttfarcken |author3=Theresa A. Kuntzweiler|author4=Clark A. Briggs |author5=David J. Anderson|author6=Jeffrey E. Campbell |author7=Marietta Piattoni-Kaplan|author8=David G. Mckenna |author9=James T. Wasicak|author10=Mark W. Holladay |author11=Michael Williams |author12=Stephen P. Arneric |last-author-amp=yes |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=285 |issue=2 |pages=777–786|url=http://jpet.aspetjournals.org/content/285/2/777.short|date=May 1998 }}</ref>
+Because of its analgesic effect, there was intense interest in epibatidine's use as a drug, because it was found not to be an opioid.<ref name="H.M. Garraffo (2009)"/> This meant that it could potentially be used without fear of addiction. However, it was soon found that it cannot be used in humans because the dose resulting in toxic symptoms is too low for it to be safe.<ref name="Donnelly-Roberts">{{cite journal | vauthors = Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, Piattoni-Kaplan M, McKenna DG, Wasicak JT, Holladay MW, Williams M, Arneric SP | display-authors = 6 | title = ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 285 | issue = 2 | pages = 777–786 | date = May 1998 | pmid = 9580626 | url = http://jpet.aspetjournals.org/content/285/2/777.short | name-list-style = amp }}</ref>
 ==Synthesis==
-Several total synthesis routes have been devised due to the relative scarcity of epibatidine in nature.<ref>{{cite journal | doi = 10.1080/00304940209355744 | last1 = Olivo | first1 = Horacio F. | last2 = Hemenway | first2 = Michael S. | year = 2002 | title = Recent syntheses of epibatidine. A review | url = | journal = Organic Preparations and Procedures International | volume = 34 | issue = 1| pages = 1–26 }}</ref>
+Several total synthesis routes have been devised due to the relative scarcity of epibatidine in nature.<ref>{{cite journal | doi = 10.1080/00304940209355744 | vauthors = Olivo HF, Hemenway MS | year = 2002 | title = Recent syntheses of epibatidine. A review | journal = Organic Preparations and Procedures International | volume = 34 | issue = 1| pages = 1–26 | s2cid = 98696766 }}</ref>
-After the discovery of the structure of epibatidine, more than fifty ways to synthesize it in the laboratory have been devised. In the first reported example, a nine-step procedure produces the substance as a [[racemate]] (in contrast, the naturally occurring compound is the (+)-enantiomer; the (−)-enantiomer does not occur naturally). 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%.<ref name="Traynor">{{cite web|url=http://bja.oxfordjournals.org/content/81/1/69.full.pdf |publisher=British Journal of Anaesthesia 1998 |volume=81 |pages=69–76 |title=Epibatidine and pain |accessdate=2014-03-12}}</ref><ref name=car/><ref name="Broka">Broka, C.A. Synthetic Approaches to Epibatidine. Med. Chem. Res. 1994, 4, 449-460.</ref>
+After the discovery of the structure of epibatidine, more than fifty ways to synthesize it in the laboratory have been devised. In the first reported example, a nine-step procedure produces the substance as a [[racemate]] (in contrast, the naturally occurring compound is the (+)-enantiomer; the (−)-enantiomer does not occur naturally). 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%.<ref name="Traynor">{{cite journal | vauthors = Traynor JR | title = Epibatidine and pain | journal = British Journal of Anaesthesia | volume = 81 | issue = 1 | pages = 69–76 | date = July 1998 | pmid = 9771274 | doi = 10.1093/bja/81.1.69 | doi-access = free }}</ref><ref name=car/><ref name="Broka">{{cite journal | vauthors = Broka CA | title = Synthetic approaches to epibatidine. | journal = Medicinal Chemistry Research | date = 1994 | volume = 4 | issue = 7 | pages = 449–460 }}</ref>
 An [[enantioselective]] synthesis reported by [[E J Corey]] starting from chloronicotinaldehyde is outlined below:
-[[File:Epibatidine Corey.svg|thumb|left|upright|600px|alt=a chemical reaction seen in the synthesis of epibatidine|The chemical synthesis of epibatidine by [[E J Corey|Corey]]]]{{clear}}
+:[[File:Epibatidine Corey.svg|thumb|left|upright|600px|alt=a chemical reaction seen in the synthesis of epibatidine|The chemical synthesis of epibatidine by [[E J Corey|Corey]]]]{{clear}}
-In addition to Corey's method, other notable methods include those of Broka,<ref>{{cite journal | author = Broka, C.A. | title = Total synthesis of epibatidine | journal = Tetrahedron Lett | volume = 34 | issue = 20 | pages = 3251–3254  | date = 1993 | doi=10.1016/s0040-4039(00)73674-4}}</ref>  Huang and Shen,<ref>{{cite journal |author1=Huang, D.F.  |author2=Shen, T.Y. | title = A versatile total synthesis of epibatidine and analogs | journal = Tetrahedron Lett | volume = 34 |issue=28 | pages = 4477–4480 | date = 1993 | doi=10.1016/0040-4039(93)88063-o}}</ref> and Clayton and Regan.<ref name=car>{{cite journal | journal = Tetrahedron Letters | volume = 34 | issue = 46 | date = 1993 | pages = 7493–7496 | title = A total synthesis of (±)-epibatidine |author1=Simon C. Clayton |author2=Andrew C. Regan | doi = 10.1016/S0040-4039(00)60162-4}}</ref>
+In addition to Corey's method, other notable methods include those of Broka,<ref>{{cite journal | vauthors = Broka CA | title = Total synthesis of epibatidine | journal = Tetrahedron Lett | volume = 34 | issue = 20 | pages = 3251–3254  | date = 1993 | doi=10.1016/s0040-4039(00)73674-4}}</ref>  Huang and Shen,<ref>{{cite journal | vauthors = Huang DF, Shen TY | title = A versatile total synthesis of epibatidine and analogs | journal = Tetrahedron Lett | volume = 34 |issue=28 | pages = 4477–4480 | date = 1993 | doi=10.1016/0040-4039(93)88063-o}}</ref> and Clayton and Regan.<ref name=car>{{cite journal | journal = Tetrahedron Letters | volume = 34 | issue = 46 | date = 1993 | pages = 7493–7496 | title = A total synthesis of (±)-epibatidine | vauthors = Clayton SC, Regan AC | doi = 10.1016/S0040-4039(00)60162-4}}</ref>
 ===Synthetic analogs===
-A number of approaches to discovering [[structural analog]]s of epibatine that maintain analgesics effects, but without the toxicity, have been attempted.<ref name="Dowd"/> For example, [[Abbott Laboratories]] has produced derivatives of epibatidine including [[ABT-594]].<ref>{{cite web|url=http://www.mongabay.com/05epidatidine.htm |title=Deriving a non-opiate painkiller [ABT-594&#93; from Epipedobates tricolor |publisher=Mongabay.com |date= |accessdate=2014-03-12}}</ref> Other epibatidine analogs include [[ABT-418]], [[epiboxidine]] and their derivatives.<ref name="Dowd">[http://www.pharmacy.vcu.edu/medchem/articles/epi/index.html] {{webarchive|url=https://web.archive.org/web/20101205015705/http://www.pharmacy.vcu.edu/medchem/articles/epi/index.html|date=December 5, 2010}}</ref><ref>{{Cite journal|last=Rizzi|first=Luca|last2=Dallanoce|first2=Clelia|last3=Matera|first3=Carlo|last4=Magrone|first4=Pietro|last5=Pucci|first5=Luca|last6=Gotti|first6=Cecilia|last7=Clementi|first7=Francesco|last8=De Amici|first8=Marco|date=2008-08-15|title=Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes|journal=Bioorganic & Medicinal Chemistry Letters|volume=18|issue=16|pages=4651–4654|doi=10.1016/j.bmcl.2008.07.016|pmid=18644719|hdl=2434/59291|url=https://air.unimi.it/bitstream/2434/59291/1/Bioorganic%20%26%20Medicinal%20Chemistry%20Letters%2018%20%282008%29%204651%e2%80%934654.pdf}}</ref><ref>{{Cite journal|last=Dallanoce|first=Clelia|last2=Matera|first2=Carlo|last3=Amici|first3=Marco De|last4=Rizzi|first4=Luca|last5=Pucci|first5=Luca|last6=Gotti|first6=Cecilia|last7=Clementi|first7=Francesco|last8=Micheli|first8=Carlo De|date=2012-07-01|title=The enantiomers of epiboxidine and of two related analogs: Synthesis and estimation of their binding affinity at α4β2 and α7 neuronal nicotinic acetylcholine receptors|journal=Chirality|language=en|volume=24|issue=7|pages=543–551|doi=10.1002/chir.22052|pmid=22566097|issn=1520-636X}}</ref><ref>{{Cite journal|last=Dallanoce|first=Clelia|last2=Matera|first2=Carlo|last3=Pucci|first3=Luca|last4=Gotti|first4=Cecilia|last5=Clementi|first5=Francesco|last6=Amici|first6=Marco De|last7=Micheli|first7=Carlo De|date=2012-01-15|title=Synthesis and binding affinity at α4β2 and α7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7-azabicyclo[2.2.1]hept-2-ene ring system|journal=Bioorganic & Medicinal Chemistry Letters|volume=22|issue=2|pages=829–832|doi=10.1016/j.bmcl.2011.12.052|pmid=22222032}}</ref><ref>{{Cite journal|last=Dallanoce|first=Clelia|last2=Magrone|first2=Pietro|last3=Matera|first3=Carlo|last4=Lo Presti|first4=Leonardo|last5=De Amici|first5=Marco|last6=Riganti|first6=Loredana|last7=Clementi|first7=Francesco|last8=Gotti|first8=Cecilia|last9=De Micheli|first9=Carlo|date=2010-12-01|title=Synthesis of novel chiral Δ2-isoxazoline derivatives related to ABT-418 and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes|journal=European Journal of Medicinal Chemistry|volume=45|issue=12|pages=5594–5601|doi=10.1016/j.ejmech.2010.09.009|pmid=20932609}}</ref> A synthesis of epibatidine, utilizing a microbial hydroxylation of an unactivated carbon in a 7-azanorbornane was published in 1999.<ref>{{Cite journal|last=Olivo|first=Horacio F.|last2=Hemenway|first2=Michael S.|date=1999-11-01|title=Total Synthesis of (±)-Epibatidine Using a Biocatalytic Approach|journal=The Journal of Organic Chemistry|volume=64|issue=24|pages=8968–8969|doi=10.1021/jo991141q|pmid=11674810|issn=0022-3263}}</ref>
+A number of approaches to discovering [[structural analog]]s of epibatine that maintain analgesics effects, but without the toxicity, have been attempted.<ref name="Dowd"/> For example, [[Abbott Laboratories]] has produced derivatives of epibatidine including [[tebanicline]] (ABT-594).<ref>{{cite web|url=http://www.mongabay.com/05epidatidine.htm |title=Deriving a non-opiate painkiller [ABT-594&#93; from Epipedobates tricolor |publisher=Mongabay.com |access-date=2014-03-12}}</ref> Tebanicline retains analgesic properties while avoiding paralysis by still binding to receptors that control pain perception and having a low affinity for muscle-type nicotinic acetylcholine receptors (nAChR) reducing its paralysis effect.<ref>{{Cite web|title=Epibatidine|url=http://www.chm.bris.ac.uk/webprojects2002/jjones/Content/Epibatidine.htm|access-date=2021-11-12| work = School of Chemistry | publisher = University of Bristol }}</ref> Other epibatidine analogs include [[ABT-418]], [[epiboxidine]], and their derivatives.<ref name="Dowd">{{cite web | vauthors = Dowd MJ | title = Epibatidine | url = http://www.pharmacy.vcu.edu/medchem/articles/epi/index.html | archive-url=https://web.archive.org/web/20101205015705/http://www.pharmacy.vcu.edu/medchem/articles/epi/index.html| archive-date=December 5, 2010 | work = Department of Medicinal Chemistry | publisher = Virginia Commonwealth University }}</ref><ref>{{cite journal | vauthors = Rizzi L, Dallanoce C, Matera C, Magrone P, Pucci L, Gotti C, Clementi F, De Amici M | display-authors = 6 | title = Epiboxidine and novel-related analogues: a convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 16 | pages = 4651–4654 | date = August 2008 | pmid = 18644719 | doi = 10.1016/j.bmcl.2008.07.016 | hdl-access = free | hdl = 2434/59291 }}</ref><ref>{{cite journal | vauthors = Dallanoce C, Matera C, De Amici M, Rizzi L, Pucci L, Gotti C, Clementi F, De Micheli C | display-authors = 6 | title = The enantiomers of epiboxidine and of two related analogs: synthesis and estimation of their binding affinity at α4β2 and α7 neuronal nicotinic acetylcholine receptors | journal = Chirality | volume = 24 | issue = 7 | pages = 543–551 | date = July 2012 | pmid = 22566097 | doi = 10.1002/chir.22052 }}</ref><ref>{{cite journal | vauthors = Dallanoce C, Matera C, Pucci L, Gotti C, Clementi F, Amici MD, Micheli CD | title = Synthesis and binding affinity at α4β2 and α7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7-azabicyclo[2.2.1]hept-2-ene ring system | journal = Bioorganic & Medicinal Chemistry Letters | volume = 22 | issue = 2 | pages = 829–832 | date = January 2012 | pmid = 22222032 | doi = 10.1016/j.bmcl.2011.12.052 }}</ref><ref>{{cite journal | vauthors = Dallanoce C, Magrone P, Matera C, Lo Presti L, De Amici M, Riganti L, Clementi F, Gotti C, De Micheli C | display-authors = 6 | title = Synthesis of novel chiral Δ2-isoxazoline derivatives related to ABT-418 and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes | journal = European Journal of Medicinal Chemistry | volume = 45 | issue = 12 | pages = 5594–5601 | date = December 2010 | pmid = 20932609 | doi = 10.1016/j.ejmech.2010.09.009 }}</ref> A synthesis of epibatidine, utilizing a microbial hydroxylation of an unactivated carbon in a 7-azanorbornane was published in 1999.<ref>{{cite journal | vauthors = Olivo HF, Hemenway MS | title = Total Synthesis of (+/-)-Epibatidine Using a Biocatalytic Approach | journal = The Journal of Organic Chemistry | volume = 64 | issue = 24 | pages = 8968–8969 | date = November 1999 | pmid = 11674810 | doi = 10.1021/jo991141q }}</ref>
 ==Chemical structure==
-Epibatidine is a [[pyridine]] with a structure similar to that of [[nicotine]].<ref name="M. Fisher">{{cite journal|vauthors=Fisher M, Huangfu D, Shen TY, Guyenet PG | title=Epibatidine, an alkaloid from the poison frog ''Epipedobates tricolor'', is a powerful ganglionic depolarizing agent. | journal=J Pharmacol Exp Ther | year= 1994 | volume= 270 | issue= 2 | pages= 702–7 | pmid=8071862 | url= http://jpet.aspetjournals.org/content/270/2/702.abstract}}</ref> It is a [[hygroscopic]] oily substance which is a [[base (chemistry)|base]].
+Epibatidine is a piperidine [[pyridine]] with a structure similar to that of [[nicotine]].<ref name="M. Fisher">{{cite journal | vauthors = Fisher M, Huangfu D, Shen TY, Guyenet PG | title = Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 270 | issue = 2 | pages = 702–707 | date = August 1994 | pmid = 8071862 | url = http://jpet.aspetjournals.org/content/270/2/702.abstract }}</ref> It is a [[hygroscopic]] oily substance which is a [[base (chemistry)|base]].
 ==Biological effects==
@@ Line 82: / Line 81: @@
 ===Mechanism of action===
-Epibatidine has two mechanisms of action: it can bind to either [[nicotinic acetylcholine receptor]]s (nAChR) or  [[muscarinic acetylcholine receptor]]s (mAChR).  Specifically, the [[analgesic]] property of epibatidine is believed to take place by its binding to the [[Alpha-4 beta-2 nicotinic receptor|α4/β2]] subtype of nicotinic receptors. Epibatidine also binds to the [[Alpha-3 beta-4 nicotinic receptor|α3/β4]] subtype and to a much lesser extent [[Alpha-7 receptor|α7 receptors]] (affinity 300-fold less than for [[Alpha-4 beta-2 nicotinic receptor|α4/β2]])<ref>{{Cite journal|last=Traynor|first=John R.|title=Epibatidine and pain|url=https://www.bjanaesthesia.org/article/S0007-0912(17)48526-6/pdf|journal=British Journal of Anaesthesia|volume=81|issue=1|pages=69–76|doi=10.1093/bja/81.1.69|pmid=9771274|via=|year=1998}}</ref> The rank order of affinities is αε > αγ > αδ.<ref>{{Cite journal|last=Prince|first=Richard J.|last2=Sine|first2=Steven M.|date=1998-04-03|title=Epibatidine Binds with Unique Site and State Selectivity to Muscle Nicotinic Acetylcholine Receptors|journal=Journal of Biological Chemistry|language=en|volume=273|issue=14|pages=7843–7849|doi=10.1074/jbc.273.14.7843|issn=0021-9258|pmid=9525877|doi-access=free}}</ref>
+Epibatidine has two mechanisms of action: it can bind to either [[nicotinic acetylcholine receptor]]s (nAChR) or  [[muscarinic acetylcholine receptor]]s (mAChR).  Specifically, the [[analgesic]] property of epibatidine is believed to take place by its binding to the [[Alpha-4 beta-2 nicotinic receptor|α4/β2]] subtype of nicotinic receptors. Epibatidine also binds to the [[Alpha-3 beta-4 nicotinic receptor|α3/β4]] subtype and to a much lesser extent [[Alpha-7 receptor|α7 receptors]] (affinity 300-fold less than for [[Alpha-4 beta-2 nicotinic receptor|α4/β2]])<ref>{{cite journal | vauthors = Traynor JR | title = Epibatidine and pain | journal = British Journal of Anaesthesia | volume = 81 | issue = 1 | pages = 69–76 | date = July 1998 | pmid = 9771274 | doi = 10.1093/bja/81.1.69 | doi-access = free }}</ref> The rank order of affinities for the muscle nicotinic receptors is αε > αγ > αδ.<ref>{{cite journal | vauthors = Prince RJ, Sine SM | title = Epibatidine binds with unique site and state selectivity to muscle nicotinic acetylcholine receptors | journal = The Journal of Biological Chemistry | volume = 273 | issue = 14 | pages = 7843–7849 | date = April 1998 | pmid = 9525877 | doi = 10.1074/jbc.273.14.7843 | doi-access = free }}</ref>
-Nicotinic acetylcholine receptors are found in the post-synaptic membranes of nerve cells. They propagate neurotransmission in the [[central nervous system|central]] and [[peripheral nervous system]]. When neurotransmitters bind to these receptors, ion channels open, allowing Na<sup>+</sup> and Ca<sup>2+</sup> ions to move across the membrane. This depolarizes the post-synaptic membrane, inducing an action potential that propagates the signal. This signal will ultimately induce release of [[dopamine]] and [[norepinephrine]], resulting in an antinociceptive effect on the organism.
+Nicotinic acetylcholine receptors are found in the post-synaptic membranes of nerve cells. These receptors are an example of ion gated channels where binding by a ligand causes a conformational change allowing ions to cross the membrane into the cell.<ref>{{cite journal | vauthors = Hogg RC, Raggenbass M, Bertrand D | title = Nicotinic acetylcholine receptors: from structure to brain function | journal = Reviews of Physiology, Biochemistry and Pharmacology | volume = 147 | pages = 1–46 | date = 2003 | pmid = 12783266 | doi = 10.1007/s10254-003-0005-1 | isbn = 978-3-540-01365-5 }}</ref> They propagate neurotransmission in the [[central nervous system|central]] and [[peripheral nervous system]]. When neurotransmitters bind to these receptors, ion channels open, allowing Na<sup>+</sup> and Ca<sup>2+</sup> ions to move across the membrane. This depolarizes the post-synaptic membrane, inducing an action potential that propagates the signal. This signal will ultimately induce release of [[dopamine]] and [[norepinephrine]], resulting in an antinociceptive effect on the organism.
 The usual neurotransmitter for nAChR is acetylcholine. However, other substances (such as epibatidine and [[nicotine]]) are also able to bind to the receptor and induce a similar, if not identical, response. Epibatidine has an extremely high affinity for nAChRs, depending on the receptor subtype, from 0.05&nbsp;nM at the α4β2 subtype to 22&nbsp;nM at the α7 subtype. [[Affinity (pharmacology)|Affinity]] as well as [[Intrinsic activity|efficacy]] (and thus also [[Potency (pharmacology)|potency]]) are much higher than for nicotine.<ref name="Traynor"/>
@@ Line 91: / Line 90: @@
 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.
-Both (+)- and (-)-[[enantiomer]]s of epibatidine are biologically active, and both have similar binding affinities to nAChRs<ref name="Traynor"/>  Only the (+)-enantiomer does not induce tolerance.  While this may be a potential therapeutic advantage over morphine, epibatidine has not entered clinical trials because even very small doses are lethal to rodents.<ref>Abby Olena. How Poison Frogs Avoid Poisoning Themselves. The Scientist, September 21, 2017H. http://www.the-scientist.com/?articles.view/articleNo/50409/title/How-Poison-Frogs-Avoid-Poisoning-Themselves/</ref>
+Both (+)- and (-)-[[enantiomer]]s of epibatidine are biologically active, and both have similar binding affinities to nAChRs<ref name="Traynor"/>  Only the (+)-enantiomer does not induce tolerance.  While this may be a potential therapeutic advantage over morphine, epibatidine has not entered clinical trials because even very small doses are lethal to rodents.<ref>{{cite web | vauthors = Olena A | title = How Poison Frogs Avoid Poisoning Themselves. | work = The Scientist | date = September 21, 2017 | url = http://www.the-scientist.com/?articles.view/articleNo/50409/title/How-Poison-Frogs-Avoid-Poisoning-Themselves/ }}</ref>
 ===Symptoms===
-Epibatidine has several toxic consequences. Empirically proven effects include [[splanchnic nerves|splanchnic]] [[sympathetic nervous system|sympathetic]] nerve discharge and increased arterial pressure.<ref name="M. Fisher"/> The nerve discharge effects can cause antinociception partially mediated by agonism of central nicotinic acetylcholine receptors at low doses of epibatidine; 5&nbsp;µg/kg.<ref name="Daly">Badio B, Daly JW. Epibatidine, a potent analgetic and nicotinic agonist, Molecular Pharmacology 1994; 45: 563-569</ref> At higher doses, however, epibatidine will cause paralysis and loss of consciousness, coma and eventually death. The [[median lethal dose]]  (LD<sub>50</sub>) of epibatidine lies between 1.46&nbsp;µg/kg and 13.98&nbsp;µg/kg.<ref>{{cite web|author=Sihver, Acta |title=Neurologica Scandinavica, Ligands for in vivo imaging on nicotinic receptor subtypes in Alzheimer brain|date=2002|url=http://www3.interscience.wiley.com/cgi-bin/fulltext/119031393/PDFSTART|publisher=Interscience.wiley.com|accessdate=2014-03-12}}{{dead link|date=February 2019|bot=medic}}{{cbignore|bot=medic}}</ref> This makes epibatidine somewhat more toxic than [[dioxin]] (with an average LD<sub>50</sub> of 22.8&nbsp;µg/kg).{{citation needed|date=May 2018}} Due to the small difference between its toxic concentration and antinociceptive concentration, its therapeutic uses are very limited.
+Epibatidine has several toxic consequences. Empirically proven effects include [[splanchnic nerves|splanchnic]] [[sympathetic nervous system|sympathetic]] nerve discharge and increased arterial pressure.<ref name="M. Fisher"/> The nerve discharge effects can cause antinociception partially mediated by agonism of central nicotinic acetylcholine receptors at low doses of epibatidine; 5&nbsp;μg/kg.<ref name="Daly">{{cite journal | vauthors = Badio B, Daly JW | title = Epibatidine, a potent analgetic and nicotinic agonist | journal = Molecular Pharmacology | volume = 45 | issue = 4 | pages = 563–9 | date = April 1994 | pmid = 8183234 | doi = | url = }}</ref> At higher doses, however, epibatidine will cause paralysis and loss of consciousness, coma and eventually death. The [[median lethal dose]]  (LD<sub>50</sub>) of epibatidine lies between 1.46&nbsp;μg/kg and 13.98&nbsp;μg/kg.<ref>{{cite journal | vauthors = Sihver W, Långström B, Nordberg A | title = Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain | journal = Acta Neurologica Scandinavica. Supplementum | volume = 176 | pages = 27–33 | date = 2002 | pmid = 11261802 | doi = 10.1034/j.1600-0404.2000.00304.x | s2cid = 23541883 | doi-access = free }}</ref> This makes epibatidine somewhat more toxic than [[dioxin]] (with an average LD<sub>50</sub> of 22.8&nbsp;μg/kg).{{citation needed|date=May 2018}} Due to the small difference between its toxic concentration and antinociceptive concentration, its therapeutic uses are very limited.
 In research on mice, administration of doses greater than 5&nbsp;μg/kg of epibatidine caused a dose-dependent paralyzing effect on the organism. With doses over 5&nbsp;μg/kg, 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.
@@ Line 101: / Line 100: @@
 ===Pharmacology===
-Epibatidine most effectively enters the body through injection.<ref name="Sullivan">{{cite journal |author1=Sullivan, J.P.  |author2=Bannon, A.W. |title=Epibatidine: Pharmacological Properties of a Novel Nicotinic Acetylcholine Receptor Agonist and Analgesic Agent |journal=CNS Drug Reviews |volume=2 |issue=1 |pages=21–39 |doi=10.1111/j.1527-3458.1996.tb00288.x|year=1996 }}</ref> [[In vitro]] studies seem to suggest that epibatidine is hardly, if at all, metabolized in the human body.<ref>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.</ref>
+Epibatidine most effectively enters the body through injection.<ref name="Sullivan">{{cite journal | vauthors = Sullivan JP, Bannon AW |title= Epibatidine: Pharmacological Properties of a Novel Nicotinic Acetylcholine Receptor Agonist and Analgesic Agent |journal=CNS Drug Reviews |volume=2 |issue=1 |pages=21–39 |doi=10.1111/j.1527-3458.1996.tb00288.x|year=1996 }}</ref> ''[[In vitro]]'' studies seem to suggest that epibatidine is hardly, if at all, metabolized in the human body.<ref name="pmid11093658">{{cite journal | vauthors = Watt AP, Hitzel L, Morrison D, Locker KL | title = Determination of the in vitro metabolism of (+)- and (-)-epibatidine | journal = Journal of Chromatography A | volume = 896 | issue = 1–2 | pages = 229–38 | date = October 2000 | pmid = 11093658 | doi = 10.1016/s0021-9673(00)00597-5 }}</ref>
 Also there is currently little information on the path of clearance from the body. Maximum concentration in the brain is reached at about 30 minutes after entering the body.<ref name="Traynor"/>
@@ Line 107: / Line 106: @@
 ===Potential medical uses===
-Epibatidine has a high analgesic potency, as stated above. Studies show it has a potency at least 200 times that of [[morphine]].<ref name="Traynor"/> As the compound was not addictive nor did it cause [[habituation#Neurobiology of Habituation|habituation]],{{citation needed|date=March 2014}}, it was initially thought to be very promising to replace morphine as a painkiller. However, the therapeutic concentration is very close to the toxic concentration. This means that even at a therapeutic dose (5&nbsp;µg/kg<ref name="Daly"/>), some epibatidine might bind to the [[muscarinic acetylcholine receptors]] and cause adverse effects, such as [[hypertension]], [[bradycardia]] and muscular [[paresis]].<ref name="M. Fisher"/>
+Epibatidine has a high analgesic potency, as stated above. Studies show it has a potency at least 200 times that of [[morphine]].<ref name="Traynor"/> As the compound was not addictive nor did it cause [[habituation#Neurobiology of Habituation|habituation]],{{citation needed|date=March 2014}}, it was initially thought to be very promising to replace morphine as a painkiller. However, the therapeutic concentration is very close to the toxic concentration. This means that even at a therapeutic dose (5&nbsp;μg/kg<ref name="Daly"/>), some epibatidine might bind to the [[muscarinic acetylcholine receptors]] and cause adverse effects, such as [[hypertension]], [[bradycardia]] and muscular [[paresis]].<ref name="M. Fisher"/>
-Compared to the gold standard in pain management, [[morphine]], epibatidine needed only 2.5&nbsp;μg/kg to initiate a pain-relieving effect whilst the same effect required approximately 10&nbsp;mg/kg 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.<ref name="Broka"/>
+Compared to the gold standard in pain management, [[morphine]], epibatidine needed only 2.5&nbsp;μg/kg (11.98 nmol/kg) to initiate a pain-relieving effect whilst the same effect required approximately 10&nbsp;mg/kg (35.05 μmol/kg) of morphine (approx. 2,900 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.<ref name="Broka"/>
 ===Antidote===
-The antidote to epibatidine is [[mecamylamine]],<ref name="Damaj">{{cite journal |author=Damaj, M.I. |display-authors=etal |title=Pharmacological effects of epibatidine optical enantiomers |journal=Brain Research |volume=664 |issue=1 |pages=34–40 |doi=10.1016/0006-8993(94)91950-x |pmid=7895043 |year=1994}}</ref> a nicotinic acetylcholine receptor antagonist that is non-selective and non-competitive.<ref name="Bacher">{{cite journal |doi=10.1517/14656560903329102 |author=Bacher, I.|title=Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders |journal=Expert Opinion on Pharmacotherapy |volume=10 |issue=16 |pages=2709–2721|display-authors=etal |pmid=19874251 |date=November 2009}}</ref>
+The antidote to epibatidine is [[mecamylamine]],<ref name="Damaj">{{cite journal | vauthors = Damaj MI, Creasy KR, Grove AD, Rosecrans JA, Martin BR | title = Pharmacological effects of epibatidine optical enantiomers | journal = Brain Research | volume = 664 | issue = 1–2 | pages = 34–40 | date = November 1994 | pmid = 7895043 | doi = 10.1016/0006-8993(94)91950-x | s2cid = 46489298 }}</ref> a nicotinic acetylcholine receptor antagonist that is non-selective and non-competitive.<ref name="Bacher">{{cite journal | vauthors = Bacher I, Wu B, Shytle DR, George TP | title = Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 16 | pages = 2709–2721 | date = November 2009 | pmid = 19874251 | doi = 10.1517/14656560903329102 | s2cid = 25690407 }}</ref> Both the (+) and the (-) enantiomers of mecamylamine were seen to be efficient and both have the same affinity for nicotinic acetylcholine receptors.<ref>{{cite journal | vauthors = Nickell JR, Grinevich VP, Siripurapu KB, Smith AM, Dwoskin LP | title = Potential therapeutic uses of mecamylamine and its stereoisomers | journal = Pharmacology, Biochemistry, and Behavior | volume = 108 | pages = 28–43 | date = July 2013 | pmid = 23603417 | pmc = 3690754 | doi = 10.1016/j.pbb.2013.04.005 }}</ref>
-==See also==
+== See also ==
+* [[6-Chloronicotine]]
 * [[Arrow poison]]
-* [[Batrachotoxin]] (and closely related [[Homobatrachotoxin]])
+* [[Batrachotoxin]] (and closely related [[homobatrachotoxin]])
+* [[Nemertelline]], neurotoxin closely related to [[nicotelline]]
-* [[Tetrodotoxin]]
 * [[Phantasmidine]]
+* [[Tetrodotoxin]]
-==References==
+== References ==
 {{Reflist|2}}
-==External links==
+== External links ==
 * [https://web.archive.org/web/20090106012913/http://www.chemsoc.org/ExemplarChem/entries/2004/icl_Pan/index.html Epibatidine at chemsoc.org]
@@ Line 135: / Line 136: @@
 [[Category:Analgesics]]
 [[Category:Nicotinic agonists]]
-[[Category:Vertebrate toxins]]
+[[Category:Amphibian toxins]]
 [[Category:Pyridine alkaloids]]
 [[Category:Halogen-containing alkaloids]]
 [[Category:Chloropyridines]]
 [[Category:Neurotoxins]]
+[[Category:Halogen-containing natural products]]
+[[Category:Chlorine-containing natural products]]

v t e Stimulants
Adamantanes	Adapromine Amantadine Bromantane Memantine Rimantadine
Adenosine antagonists	8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Istradefylline Paraxanthine SCH-58261 Theobromine Theophylline
Alkylamines	Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane
Ampakines	CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram
Arylcyclohexylamines	Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine
Benzazepines	6-Br-APB SKF-77434 SKF-81297 SKF-82958
Cathinones	3-FMC 3-MMC 3,4-DMMC 4-BMC 4-CMC 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-Methylpentedrone Amfepramone Benzedrone Buphedrone Bupropion Butylone Cathinone Dimethylcathinone Ethcathinone Ethylone Flephedrone Hexedrone Isoethcathinone Mephedrone Methcathinone Methedrone Methylenedioxycathinone Methylone Mexedrone N-Ethylbuphedrone N-Ethylhexedrone Pentedrone Pentylone Phthalimidopropiophenone
Cholinergics	A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538
Convulsants	Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone
Eugeroics	Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol Modafinil
Oxazolines	4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone
Phenethylamines	1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fluoroamphetamine 2-Fluoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fluoroamphetamine 3-Fluoroethamphetamine 3-Methoxyamphetamine 3-Methylamphetamine 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-MMA 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Camfetamine Cathine Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethylnorepinephrine Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine Fludorex Formetorex Furfenorex Gepefrine Hexapradol HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methoxyphenamine MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol (Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine
Phenylmorpholines	3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine
Piperazines	2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 JJC8-088 MeOPP MBZP oMPP Vanoxerine
Piperidines	1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate JZ-IV-10 Methylphenidate (Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate Serdexmethylphenidate SCH-5472
Pyrrolidines	2-Diphenylmethylpyrrolidine 4-Cl-PVP 5-DBFPV α-PPP α-PBP α-PCYP α-PHiP α-PHP α-PHPP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone
Racetams	Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide
Tropanes	4-fluorotropacocaine 4'-Fluorococaine Altropane (IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane (RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (¹²³I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121 (IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil (β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33
Tryptamines	4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT
Others	2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine
ATC code: N06B

v t e Neurotoxins
Animal toxins	Batrachotoxin Bestoxin Birtoxin Bungarotoxin Charybdotoxin Conotoxin Fasciculin Huwentoxin Poneratoxin Saxitoxin Tetrodotoxin Vanillotoxin Spooky toxin (SsTx) Epibatidine Zetekitoxin AB Dendrotoxin
Bacterial	Botulinum toxin Tetanospasmin
Cyanotoxins	Anatoxin-a Guanitoxin BMAA Saxitoxin
Plant toxins	Aconitine Bicuculline Penitrem A Picrotoxin Strychnine Tutin Rotenone Ginkgotoxin Cicutoxin Oenanthotoxin Thujone Volkensin Veratridine
Mycotoxins	Ibotenic acid Muscarine Muscimol
Pesticides	Fenpropathrin Tetramethylenedisulfotetramine Bromethalin Crimidine Methamidophos Endosulfan Fipronil Phenylsilatrane Chlorophenylsilatrane Sulfuryl fluoride Mipafox Schradan Dimefox
Nerve agents	Cyclosarin EA-3148 Novichok agent Sarin Soman Tabun VE VG VM VP VR VX GV EA-3990 EA-4056 T-1123 Octamethylene-bis(5-dimethylcarbamoxyisoquinolinium bromide) Fluorotabun Chinese VX EA-2192
Bicyclic phosphates	TBPS TBPO IPTBO
Cholinergic neurotoxins	Acetylcholine mustard Catecholine Choline mustard Ethylcholine mustard Hemicholinium mustard
Psychoactive drugs	Alcohol Nitrous oxide
Other	Dimethylcadmium Dimethylmercury Toxopyrimidine IDPN Tetraethyllead