View source for 4-Aminopyridine

{{chembox
| Watchedfields = changed
| verifiedrevid = 308367008
|ImageFile=4-aminopyridine.svg
|ImageSize=80px
|IUPACName=pyridin-4-amine
|OtherNames=4-pyridinamine, 4-Pyridylamine, Fampridine
|Section1= {{Chembox Identifiers
|  CASNo_Ref = {{cascite}}
| CASNo=504-24-5
|  PubChem=1727
| IUPHAR_ligand = 2416
|  SMILES=C1=CN=CC=C1N
|  MeSHName=4-Aminopyridine
  }}
|Section2= {{Chembox Properties
|  Formula=C<sub>5</sub>H<sub>6</sub>N<sub>2</sub>
|  MolarMass=94.1146
|  Appearance=colourless solid
|  Density=
|  MeltingPt=155-158 °C
|  BoilingPtC=273
|  Solubility= polar organic solvents
  }}
|Section3= {{Chembox Hazards
|  MainHazards=
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|  Autoignition=
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| Section5 = {{Chembox Pharmacology
|  AdminRoutes = Oral
|  Bioavail = 96%
|  Metabolism = 
|  HalfLife = 
|  ProteinBound =
|  Excretion = 
|  Legal_status = 
|  Legal_US = Rx-only
|  Legal_UK = 
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|  PregCat = 
|  PregCat_AU = 
|  PregCat_US = C}}
}}

'''4-Aminopyridine''' (dalfampridine) is an [[organic compound]] with the [[chemical formula]] H<sub>2</sub>NC<sub>5</sub>H<sub>4</sub>N.  The molecule is one of the three isomeric [[amine]]s of [[pyridine]].  It is used primarily as a research tool, in characterizing subtypes of [[potassium channel]], and has also been used to manage some of the symptoms of [[multiple sclerosis]],<ref>{{cite journal |author=Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C |title=Aminopyridines for symptomatic treatment in multiple sclerosis |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD001330 |year=2001 |pmid=11687106 |doi=10.1002/14651858.CD001330}}</ref><ref>{{cite journal |author=Korenke AR, Rivey MP, Allington DR |title=Sustained-release fampridine for symptomatic treatment of multiple sclerosis |journal=Ann Pharmacother |volume=42 |issue=10 |pages=1458–65 |year=2008 |month=October |pmid=18780812 |doi=10.1345/aph.1L028}}</ref> for which it has [[orphan drug]] status in the United States under the [[International Nonproprietary Name|INN]] '''fampridine''' (trade name '''Neurelan'''). It was undergoing [[clinical trial#Phase III|Phase&nbsp;III]] [[clinical trial]]s {{as of|2008|lc=on}},<ref>http://www.acorda.com/pipeline_fampridine_sci1.asp</ref> and the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) approved the compound on January 22, 2010.<ref name=FDA>[http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm198463.htm FDA Approves Ampyra to Improve Walking in Adults with Multiple Sclerosis]</ref> Dalfampridine is marketed as '''Ampyra''' (pronounced "am-PEER-ah," according to the maker's website) in the United States by [[Acorda Therapeutics]] and will be available in March 2010.<ref name=FDA /><ref>http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2586</ref>

==Production==
4-Aminopyridine (4-AP) is prepared by the decarbonylation of pyridine-4-carboxamide using sodium hypochlorite via the [[Hofmann rearrangement]].  The pyridine carboxamide is generated from the corresponding [[nitrile]], which in turn is obtained from ammoxidation of [[4-Methylpyridine|4-methylpyridine]].<ref name=Ullmann>Shinkichi Shimizu, Nanao Watanabe, Toshiaki Kataoka, Takayuki Shoji, Nobuyuki Abe, Sinji Morishita, Hisao Ichimura "Pyridine and Pyridine Derivatives" in "Ullmann's Encyclopedia of Industrial Chemistry" 2007; John Wiley & Sons: New York.</ref>

==Applications==
The largest scale industrial application of 4-aminopyridine is as a precursor to the drug [[pinacidil]], which affects potassium ion channels.

In the laboratory, 4-AP is a useful pharmacological tool in studying various potassium conductances in physiology and biophysics. It is a relatively selective blocker of members of Kv1 ([[Shaker gene|Shaker]], KCNA) family of voltage-activated K+ channels. At concentration of 1 mM it selectively and reversibly inhibits Shaker channels without significant effect on other sodium, calcium, and potassium conductances. 

===Vertebrate Pesticide===
4-Aminopyridine is also used as a [[bird control]] agent, under the trade name Avitrol; it causes convulsions and typically death, depending on dosage<ref>EPA Reregistration Eligiblity Decision for 4-aminopyridine, pg.23, September 27, 2007.</ref>. The use of 4-aminopyridine in bird control has been criticized by the [[Humane Society of the United States]].<ref>{{cite web |url=http://www.hsus.org/wildlife/urban_wildlife_our_wild_neighbors/solving_problems/avitrol.html |title=Poisonous Solution: The Avitrol Problem |last=Brasted |first=Maggie |date=May 13, 2008 |publisher=[[Humane Society of the United States]]}} Retrieved on December 23, 2008.</ref>

===Medical use===
Fampridine has been used clinically in [[Lambert-Eaton myasthenic syndrome]] and [[multiple sclerosis]]. It acts by blocking potassium channels, prolonging [[action potentials]] and thereby increasing neurotransmitter release at the [[neuromuscular junction]].<ref>{{cite journal |author=Judge S, Bever C |title=Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment |journal=Pharmacol. Ther. |volume=111 |issue=1 |pages=224–59 |year=2006 |pmid=16472864 |doi=10.1016/j.pharmthera.2005.10.006}}</ref>
The drug has been shown to reverse [[tetrodotoxin]] toxicity in animal experiments.<ref>[http://www.emedicine.com/emerg/topic342.htm Octopus Envenomations] at eMedicine.com</ref>

====Multiple sclerosis====
{{Refimprovesect|date=December 2008}}
Fampridine has been shown to improve visual function and motor skills and relieve fatigue in patients with [[Multiple Sclerosis]] (MS). 4-AP is most effective in patients with the chronic progressive form of MS, in patients who are temperature sensitive, and in patients who have had MS for longer than three years. Common side effects include dizziness, nervousness and nausea, and the incidence of adverse effects was shown to be less than 5% in all studies.

4-AP works as a potassium channel blocker. Electrophysiologic studies of demyelinated axons show that augmented potassium currents increase extracellular potassium ion concentration which decreases action potential duration and amplitude which may cause conduction failure. Potassium channel blockade reverses this effect. However, a recent study has shown that 4-AP is a potent calcium channel activator and can improve synaptic and neuromuscular function by directly acting on the calcium channel beta subunit (J Biol Chem. 2009 Dec 25;284(52):36453-61).

MS patients treated with 4-AP exhibited a response rate of 29.5% to 80%. A long-term study (32 months) indicated that 80-90% of patients who initially responded to 4-AP exhibited long-term benefits. Although improving symptoms, 4-AP does not inhibit progression of MS.

Spinal cord injury patients have also seen improvement with 4-AP therapy. These improvements include sensory, motor and pulmonary function, with a decrease in spasticity and pain.<ref>{{cite journal |doi=10.1097/00002826-199306000-00002 |author=Van Diemen HA, Polman CH, Koetsier JC, Van Loenen AC, Nauta JJ, Bertelsmann FW |title=4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety |journal=Clinical Neuropharmacology |volume=16 |issue=3 |pages=195–204 |year=1993 |pmid=8504436}}</ref>

====Overdose====
Case reports have shown that overdoses with 4-AP can lead to [[paresthesia]]s, [[seizure]]s,<ref>{{cite journal |author=Pickett T, Enns R |title=Atypical presentation of 4-aminopyridine overdose |journal=Annals of emergency medicine |volume=27 |issue=3 |pages=382–5 |year=1996 |pmid=8599505 |doi=10.1016/S0196-0644(96)70277-9}}</ref> and [[atrial fibrillation]].<ref>{{cite journal |author=Johnson N, Morgan M |title=An unusual case of 4-aminopyridine toxicity |journal=The Journal of emergency medicine |volume=30 |issue=2 |pages=175–7 |year=2006 |pmid=16567254 |doi=10.1016/j.jemermed.2005.04.020}}</ref>

==Branding==
The drug was originally intended, by Acorda Therapeutics, to have the brand name ''Amaya'', however the name was changed to ''Ampyra'' to avoid potential confusion with other marketed pharmaceuticals.<ref>http://www.medscape.com/viewarticle/715722</ref>

==See also==
*[[4-Dimethylaminopyridine]], a popular laboratory reagent, is prepared directly from pyridine instead of via methylating this compound.<ref name=Ullmann/>
*[[Pyridine]]

==References==
{{reflist|2}}

==External links==
* [http://www.ampyra.com/hcp/ Ampyra official site]
* [http://www.ampyra.com/local/files/PI.pdf Ampyra Prescribing information]
* [http://www.avitrol.com/about.php Avitrol official site]

{{Potassium channel blockers}}

{{DEFAULTSORT:Aminopyridine, 4-}}
[[Category:Potassium channel blockers]]
[[Category:Pyridines]]
[[Category:Amines]]
[[Category:Orphan drugs]]

[[de:Aminopyridine]]
[[Category:2Fix]]