4-Aminopyridine

4-Aminopyridine
IUPAC name pyridin-4-amine
Other names 4-pyridinamine, 4-Pyridylamine, Fampridine
Identifiers
CAS number	504-24-5 Y
PubChem	1727
ChemSpider	1664 Y
UNII	BH3B64OKL9 Y
KEGG	D04127 Y
MeSH	4-Aminopyridine
ChEBI	CHEBI:34385 Y
ChEMBL	CHEMBL284348 Y
IUPHAR ligand	2416
ATC code	N07XX07
Jmol-3D images	Image 1
SMILES n1ccc(N)cc1
InChI InChI=1S/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7) Y Key: NUKYPUAOHBNCPY-UHFFFAOYSA-N Y InChI=1/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7) Key: NUKYPUAOHBNCPY-UHFFFAOYAH
Properties
Molecular formula	C5H6N2
Molar mass	94.1146
Appearance	colourless solid
Melting point	155-158 °C
Boiling point	273 °C, 546 K, 523 °F
Solubility in water	polar organic solvents
Pharmacology
Bioavailability	96%
Routes of administration	Oral
Legal status	℞-only(US)
Pregnancy category	C(US)
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

4-Aminopyridine (dalfampridine) is an organic compound with the chemical formula H₂NC₅H₄N. The molecule is one of the three isomeric amines 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,^[1][2], and is indicated for symptomatic improvement of walking in adults with several variations of the disease.^[3] The drug has orphan drug status in the United States under the INN fampridine (trade name Neurelan). It was undergoing Phase III clinical trials as of 2008^[update],^[4] and the U.S. Food and Drug Administration (FDA) approved the compound on January 22, 2010.^[5] 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.^[5][6]

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.^[7]

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, 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.^[8] The use of 4-aminopyridine in bird control has been criticized by the Humane Society of the United States.^[9]

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.^[10] The drug has been shown to reverse tetrodotoxin toxicity in animal experiments.^[11]

Multiple sclerosis

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.^[12]

Overdose

Case reports have shown that overdoses with 4-AP can lead to paresthesias, seizures,^[13] and atrial fibrillation.^[14]

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.^[15]

See also

• 4-Dimethylaminopyridine, a popular laboratory reagent, is prepared directly from pyridine instead of via methylating this compound.^[7]
• Pyridine

References

1. ^ Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C (2001). Solari, Alessandra. ed. "Aminopyridines for symptomatic treatment in multiple sclerosis". Cochrane Database Syst Rev (4): CD001330. doi:10.1002/14651858.CD001330. PMID 11687106. 
2. ^ Korenke AR, Rivey MP, Allington DR (October 2008). "Sustained-release fampridine for symptomatic treatment of multiple sclerosis". Ann Pharmacother 42 (10): 1458–65. doi:10.1345/aph.1L028. PMID 18780812. 
3. ^ "New Drugs: Fampridine". Australian Prescriber (34): 119–123. August 2011. http://www.australianprescriber.com/magazine/34/4/119/123/new-drugs-962/fampridine. 
4. ^ http://www.acorda.com/pipeline_fampridine_sci1.asp
5. ^ ^{a b} FDA Approves Ampyra to Improve Walking in Adults with Multiple Sclerosis
6. ^ http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2586
7. ^ ^{a b} 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.
8. ^ EPA Reregistration Eligiblity Decision for 4-aminopyridine, pg.23, September 27, 2007.
9. ^ Brasted, Maggie (May 13, 2008). "Poisonous Solution: The Avitrol Problem". Humane Society of the United States. http://www.hsus.org/wildlife/urban_wildlife_our_wild_neighbors/solving_problems/avitrol.html.  Retrieved on December 23, 2008.
10. ^ Judge S, Bever C (2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacol. Ther. 111 (1): 224–59. doi:10.1016/j.pharmthera.2005.10.006. PMID 16472864. 
11. ^ Octopus Envenomations at eMedicine.com
12. ^ Van Diemen HA, Polman CH, Koetsier JC, Van Loenen AC, Nauta JJ, Bertelsmann FW (1993). "4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety". Clinical Neuropharmacology 16 (3): 195–204. doi:10.1097/00002826-199306000-00002. PMID 8504436. 
13. ^ Pickett T, Enns R (1996). "Atypical presentation of 4-aminopyridine overdose". Annals of emergency medicine 27 (3): 382–5. doi:10.1016/S0196-0644(96)70277-9. PMID 8599505. 
14. ^ Johnson N, Morgan M (2006). "An unusual case of 4-aminopyridine toxicity". The Journal of emergency medicine 30 (2): 175–7. doi:10.1016/j.jemermed.2005.04.020. PMID 16567254. 
15. ^ http://www.medscape.com/viewarticle/715722

External links

• Ampyra official site
• Ampyra Prescribing information
• Avitrol official site