View source for Epibatidine

{{Short description|Toxic chemical from some poison dart frogs}}
{{Distinguish|Eptifibatide}}
{{Infobox drug
| Verifiedfields     = changed
| Watchedfields      = changed
| verifiedrevid      = 443729000
| IUPAC_name         = (1''R'',2''R'',4''S'')-(+)-6-(6-Chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane
| image              = Epibatidine structure.svg
| image_class        = skin-invert-image
| image2             = Epibatidine molecule ball.png
<!--Clinical data-->| tradename          = 
| pregnancy_category = 
| legal_status       = 
| routes_of_administration = <!--Pharmacokinetic data-->
| bioavailability    = 
| protein_bound      = 
| metabolism         = 
| elimination_half-life = 
| excretion          = <!--Identifiers-->
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 140111-52-0
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = M6K314F1XX
| ATC_prefix         = 
| ATC_suffix         = 
| PubChem            = 1204
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB07720
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 10399316
| 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
| smiles             = ClC1=CC=C([C@@H]2C[C@]3([H])CC[C@@]2([H])N3)C=N1
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| 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]]'' 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 | bibcode = 2010JNAtP..73..331F }}</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>

Epibatidine is a neurotoxin that interferes 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 causes full body numbness, which can rapidly progress to full body 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 ''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 [[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 | 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 | doi = 10.1016/S0022-3565(24)37422-1 | pmid = 9580626 | url = http://jpet.aspetjournals.org/content/285/2/777.short | name-list-style = amp | url-access = subscription }}</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 | 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 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|class=skin-invert-image|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 | 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 [[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 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 | doi = 10.1016/S0022-3565(25)22428-4 | pmid = 8071862 | url = http://jpet.aspetjournals.org/content/270/2/702.abstract | url-access = subscription }}</ref> It is a [[hygroscopic]] oily substance which is a [[base (chemistry)|base]].

==Biological effects==

===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 | 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. 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"/>

The [[paralytic]] property of epibatidine takes place after its binding to [[muscle-type nicotinic receptor]]s.

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>{{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">{{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 = 10.1016/S0026-895X(25)10139-9| 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 [[2,3,7,8-Tetrachlorodibenzodioxin|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.

===Pharmacology===

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"/>

===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"/>

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 | 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 appear to reverse the effect of this alkaloid.<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 ==
* [[6-Chloronicotine]]
* [[Arrow poison]]
* [[Batrachotoxin]] (and closely related [[homobatrachotoxin]])
* [[Nemertelline]], neurotoxin closely related to [[nicotelline]]
* [[Phantasmidine]]
* [[Tetrodotoxin]]

== References ==
{{Reflist|2}}

== External links ==
* [https://web.archive.org/web/20090106012913/http://www.chemsoc.org/ExemplarChem/entries/2004/icl_Pan/index.html Epibatidine at chemsoc.org]

{{Stimulants}}
{{Analgesics}}
{{Poison frog alkaloids}}
{{Nicotinic acetylcholine receptor modulators}}
{{Neurotoxins}}

[[Category:Analgesics]]
[[Category:Nicotinic agonists]]
[[Category:Amphibian toxins]]
[[Category:Pyridine alkaloids]]
[[Category:Halogen-containing alkaloids]]
[[Category:Chloropyridines]]
[[Category:Neurotoxins]]
[[Category:Chlorine-containing natural products]]
[[Category:Stimulants]]
[[Category:Disubstituted pyridines]]