4-Aminopyridine

4-Aminopyridine
Names
Preferred IUPAC name
Pyridin-4-amine
Other names
4-Pyridinamine
4-Pyridylamine
Fampridine
Identifiers
504-24-5 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:34385 YesY
ChEMBL ChEMBL284348 YesY
ChemSpider 1664 YesY
ECHA InfoCard 100.007.262
2416
KEGG D04127 YesY
MeSH 4-Aminopyridine
PubChem 1727
UNII BH3B64OKL9 YesY
Properties
C5H6N2
Molar mass 94.1146 g/mol
Appearance colourless solid
Melting point 155 to 158 °C (311 to 316 °F; 428 to 431 K)
Boiling point 273 °C (523 °F; 546 K)
polar organic solvents
Pharmacology
N07XX07 (WHO)
Legal status
  • US: C (Risk not ruled out)
Oral
Pharmacokinetics:
96%
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references
4-Aminopyridine

4-Aminopyridine (4-AP, INN fampridine, USAN dalfampridine) is an organic compound with the chemical formula C5H4N–NH2. The molecule is one of the three isomeric amines of pyridine. It is used as a research tool, in characterizing subtypes of the potassium channel. It has also been used as a drug, 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] It was undergoing Phase III clinical trials as of 2008,[4] and the U.S. Food and Drug Administration (FDA) approved the compound on January 22, 2010.[5] Fampridine is also marketed as Ampyra (pronounced "am-PEER-ah," according to the maker's website) in the United States by Acorda Therapeutics[5][6] and as Fampyra in Europe. In Canada, the medication has been approved for use by Health Canada since February 10, 2012.[7]

Production

4-Aminopyridine 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.[8]

Applications

The largest scale industrial application of 4-aminopyridine is as a precursor to the drug pinacidil, which affects potassium ion channels. The sequel to pinacidil, Naminidil was also derived from 4-aminopyridine. This is used as a hair growth stimulant.

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.

Convulsant activity

4-Aminopyridine is a potent convulsant and is used to generate seizures in animal models for the evaluation of antiseizure agents [9]

Vertebrate pesticide

4-Aminopyridine is also used under the trade name Avitrol as 0.5% or 1% in bird control bait. It causes convulsions and, infrequently, death, depending on dosage.[10] The manufacturer says the proper dose should cause epileptic-like convulsions which cause the poisoned birds to emit distress calls resulting in the flock leaving the site; if the dose was sub-lethal, the birds will recover after 4 or more hours without long-term ill effect.[11] The amount of bait should be limited so that relatively few birds are poisoned, causing the remainder of the flock to be frightened away with a minimum of mortality. A lethal dose will usually cause death within an hour.[11] The use of 4-aminopyridine in bird control has been criticized by the Humane Society of the United States.[12]

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.[13] The drug has been shown to reverse saxitoxin and tetrodotoxin toxicity in tissue and animal experiments.[14][15][16][17]

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. A 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.[18]

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

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.[19]

Parkinson's Disease

Dalfampridine completed Phase 2 clinical trials for Parkinson's disease in July 2014.[20]

Tetrodotoxin poisoning

Clinical studies have shown that 4-AP is capable of reversing the effects of tetrodotoxin poisoning in animals, however, its effectiveness as an antidote in humans has not yet been determined.[14][15][16]

Overdose

Case reports have shown that overdoses with 4-AP can lead to paresthesias, seizures,[21] and atrial fibrillation.[22]

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.[23]

See also

References

  1. ↑ Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C (2001). Solari A, 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.
  4. ↑ http://www.acorda.com/pipeline_fampridine_sci1.asp
  5. 1 2 FDA Approves Ampyra to Improve Walking in Adults with Multiple Sclerosis
  6. ↑ http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2586
  7. ↑ Notice of Decision for FAMPYRA
  8. 1 2 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.
  9. ↑ Yamaguchi S, Rogawski MA (1992). "Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice". Epilepsy Res. 11 (1): 9–16. doi:10.1016/0920-1211(92)90016-m. PMID 1563341.
  10. ↑ EPA Reregistration Eligibility Decision for 4-aminopyridine, pg.23, September 27, 2007.
  11. 1 2 "What is Avitrol?". Avitrol Corporation, Tulsa, Oklahoma, USA. Retrieved 15 August 2012.
  12. ↑ Brasted, Maggie (May 13, 2008). "Poisonous Solution: The Avitrol Problem". Humane Society of the United States. Retrieved on December 23, 2008.
  13. ↑ 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.
  14. 1 2 Benton, B. J.; Keller, S. A.; Spriggs, D. L.; Capacio, B. R.; Chang, F. C. (1998). "Recovery from the lethal effects of saxitoxin: A therapeutic window for 4-aminopyridine (4-AP)". Toxicon. 36 (4): 571–588. doi:10.1016/s0041-0101(97)00158-x. PMID 9643470.
  15. 1 2 Chang, F. C.; Spriggs, D. L.; Benton, B. J.; Keller, S. A.; Capacio, B. R. (1997). "4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs". Fundamental and Applied Toxicology. 38 (1): 75–88. doi:10.1006/faat.1997.2328. PMID 9268607.
  16. 1 2 Chen, H.; Lin, C.; Wang, T. (1996). "Effects of 4-Aminopyridine on Saxitoxin Intoxication". Toxicology and Applied Pharmacology. 141 (1): 44–48. doi:10.1006/taap.1996.0258. PMID 8917674.
  17. ↑ Octopus Envenomations at eMedicine.com
  18. ↑ Wu, ZZ; Li, DP; Chen, SR; Pan, HL (2009). "Aminopyridines Potentiate Synaptic and Neuromuscular Transmission by Targeting the Voltage-activated Calcium Channel β Subunit". The Journal of Biological Chemistry. 284 (52): 36453–61. doi:10.1074/jbc.M109.075523. PMC 2794761Freely accessible. PMID 19850918.
  19. ↑ 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.
  20. ↑ A Randomized Trial to Evaluate Ampyra for Gait Impairment in Parkinson's Disease
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ http://www.medscape.com/viewarticle/715722
  24. ↑ Gardner, T. S.; Wenis, E.; Lee, J. (1954). "The Synthesis of Compounds for the Chemotherapy of Tuberculosis. Iv. The Amide Function". The Journal of Organic Chemistry. 19 (5): 753. doi:10.1021/jo01370a009.

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