Chemistry:Naratriptan

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Naratriptan, sold under the brand names Amerge and Naramig among others, is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. It is a selective serotonin 5-HT1 receptor family agonist.

It was patented in 1987 and approved for medical use in 1997.[1]

Medical uses

Naratriptan is used for the treatment of the acute migraine attacks and the symptoms of migraine, including severe, throbbing headaches that sometimes are accompanied by nausea and sensitivity to sound or light.[2]

Efficacy

A meta-analysis of 53 clinical trials has shown that all triptans are effective for treating migraine at marketed doses and that naratriptan, although less effective than sumatriptan and rizatriptan was more effective than placebo in reducing migraine symptoms at two hours[3] and efficacy was demonstrated in almost two thirds of subjects after four hours of treatment.[4]

Side effects

Side effects are similar to other triptan medications, with the incidence of side effects reportedly being lower than sumatriptan, and side effects occurring rarely except when above 2.5mg.[5][6] The risk of triptan side effects is also in general low, according to a systematic review.[7] Side effects include: sensations of warmth/heat, dizziness, drowsiness, tingling of the hands or feet, nausea, dry mouth and unsteadiness, chest pain/pressure, throat pain/pressure, unusually fast/slow/irregular pulse, and mental/mood changes.[6] The tingling and heaviness and sensation of warmth/heat is characteristic of selective 5-HT1 agonists.[6]

Pharmacology

Mechanism of action

Naratriptan activities
Target Affinity (Ki, nM)
5-HT1A 15–79 (Ki)
302–>10,000 (EC50)
65–79% (Emax)
5-HT1B 0.47–9.4 (Ki)
1.4–25 (EC50)
80–98% (Emax)
5-HT1D 0.50–5.0 (Ki)
0.91–4.4 (EC50)
67–103% (Emax)
5-HT1E 7.4–20 (Ki)
6.8–31 (EC50)
97% (Emax)
5-HT1F 1.8–43 (Ki)
4.2–367 (EC50)
98% (Emax)
5-HT2A >10,000 (Ki)
>10,000 (EC50)
5-HT2B 8,320 (Ki)
>10,000 (EC50)
5-HT2C >3,160 (Ki)
ND (EC50)
5-HT3 >3,160 (mouse)
5-HT4 >3,160 (guinea pig)
5-HT5A 3,390 (rat)
5-HT6 >3,160
5-HT7 1,170–>3,160 (Ki)
>10,000 (EC50)
α1A–α1D ND
α2A–α2C ND
β1–β3 ND
D1–D5 ND
H1–H4 ND
M1–M5 ND
I1, I2 ND
σ1, σ2 ND
TAAR1 ND
SERT ND
NET ND
DAT ND
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [8][9][10][11][12][13][14][15]
[16][17][18][19][20][21][22][23]

The causes of migraine are not clearly understood; however, the efficacy of naratriptans and other triptans is believed to be due to their activity as 5-HT (serotonin) agonists. The biological and pharmacokinetic profile of naratriptan differs significantly from sumatriptan.[6]

Chemistry

Naratriptan is a triptan and a modified analogue of tryptamines like the psychedelic drug dimethyltryptamine (DMT).[24] However, naratriptan itself is not technically a tryptamine as it features a (1-methylpiperidin-4-yl) side chain instead of the ethylamine side chain present in tryptamines.[24] Besides this difference, naratriptan is substituted at the 5 position of the indole ring system and the amine moiety has been cyclized.[24] Instead of being a tryptamine, naratriptan is a piperidinylindole.[24]

The experimental log P of naratriptan is 1.6 to 2.16 and its predicted log P is 0.28 to 2.16.[25][24][26]

History

Naratriptan was patented in 1987 and was introduced for medical use in 1997.[1]

Society and culture

In the United States, the Food and Drug Administration (FDA) approved naratriptan on February 11, 1998.[27] It was covered by U.S. Patent no. 4997841; the FDA lists the patent as expiring on July 7, 2010.[27][28]

In July 2010, in the wake of the patent expiration, several drug manufacturers, including Roxane Labs,[29] Sandoz[30] and Teva Pharmaceuticals,[31] announced that they were launching generic Naratriptan medications.

The drug continued to be covered by European patent 0303507 in Germany, Spain, France and the United Kingdom through March 10, 2012,[32] and by Australian patent 611469 in Australia through June 17, 2013.[32] It had previously been covered by Canadian patent 1210968; but both Sandoz and Teva (formerly Novopharm) have offered generic equivalents in Canada since that patent's expiration December 1, 2009.[32]

On December 23, 2014, in response to a request from Health Canada, importers in Canada agreed to quarantine the importation of health products, including generic Naratriptan manufactured for both Sandoz and Teva, from Dr. Reddy's Laboratories in Srikakulam, India.[33][34] Because Teva and Sandoz are the only approved suppliers of generic Naratriptan in Canada, the quarantine resulted in Naratriptan being placed on the Canadian drug shortage list.[35]

Following the Canadian quarantine, the United Arab Emirates' Ministry of Health also imposed a similar quarantine.[35][36]

See also

References

  1. ↑ 1.0 1.1 (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 531. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA531. 
  2. ↑ "Naratriptan". Medline Plus Drug Information. U.S. National Library of Medicine. https://www.medlineplus.gov/druginfo/meds/a601083.html. 
  3. ↑ "Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials". Cephalalgia: An International Journal of Headache 22 (8): 633–58. October 2002. doi:10.1046/j.1468-2982.2002.00404.x. PMID 12383060. 
  4. ↑ "Efficacy of naratriptan tablets in the acute treatment of migraine: a dose-ranging study.". Clinical Therapeutics 22 (8): 970–80. August 2000. doi:10.1016/S0149-2918(00)80068-5. PMID 10972633. 
  5. ↑ Massiou, H (2001). "Naratriptan". Current Medical Research and Opinion 17 (1): 51–53. doi:10.1185/0300799039117016. ISSN 1473-4877. PMID 12463278. https://doi.org/10.1185/0300799039117016. 
  6. ↑ 6.0 6.1 6.2 6.3 Mathew, Ninan T (May 1999). "Naratriptan: a review" (in en). Expert Opinion on Investigational Drugs 8 (5): 687–695. doi:10.1517/13543784.8.5.687. ISSN 1354-3784. PMID 15992123. http://www.tandfonline.com/doi/full/10.1517/13543784.8.5.687. 
  7. ↑ "Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability". Headache 47 (8): 1152–68. 2007. doi:10.1111/j.1526-4610.2007.00849.x. PMID 17883520. 
  8. ↑ "Kᵢ Database". 19 July 2025. https://pdspdb.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=1291&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D=. 
  9. ↑ Liu, Tiqing. "BindingDB BDBM50073682 CHEMBL1278::N-methyl-2-(3-(1-methylpiperiden-4-yl)indole-5-yl)ethanesulfonamide::N-methyl-2-[3-(1-methyl-4-piperidyl)-1H-indol-5-yl-ethanesulfonamide::N-methyl-2-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonamide::NARATRIPTAN"]. https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50073682. 
  10. ↑ "Pharmacology of triptans". Emerging Drugs 4 (1): 107–125. 1999. doi:10.1517/14728214.4.1.107. ISSN 1361-9195. 
  11. ↑ "Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy". Drugs 60 (6): 1259–1287. December 2000. doi:10.2165/00003495-200060060-00003. PMID 11152011. 
  12. ↑ "Current and emerging second-generation triptans in acute migraine therapy: a comparative review". J Clin Pharmacol 40 (7): 687–700. July 2000. doi:10.1177/00912700022009431. PMID 10883409. 
  13. ↑ "Success and failure of triptans". The Journal of Headache and Pain 2 (1): 3–11. 2001. doi:10.1007/s101940170040. ISSN 1129-2369. 
  14. ↑ "Coronary Side Effects of Antimigraine Drugs From Patient to Receptor". 22 December 1999. https://repub.eur.nl/pub/16171/. "Table 1.2 Receptor binding properties (pKi values) of sumatriptan and second-generation triptans at 5-HT receptors. [...]" 
  15. ↑ "Vascular Effects of Antimigraine Drugs: pharmacology of human in vitro models in migraine". 13 March 2002. https://repub.eur.nl/pub/16167/. "Table 1.2 Receptor binding properties (pKi values) of the triptans at human 5-HT receptors. [...]" 
  16. ↑ "How efficacious are 5-HT1B/D receptor ligands: an answer from GTP gamma S binding studies with stably transfected C6-glial cell lines". Neuropharmacology 36 (4–5): 499–512. 1997. doi:10.1016/s0028-3908(96)00170-0. PMID 9225275. 
  17. ↑ "Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan". Cephalalgia 30 (10): 1159–1169. October 2010. doi:10.1177/0333102410370873. PMID 20855361. 
  18. ↑ "Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan". British Journal of Pharmacology 176 (24): 4681–4695. December 2019. doi:10.1111/bph.14832. PMID 31418454. "TABLE 1 Summary of pIC50 (negative logarithm of the molar concentration of these compounds at which 50% of the radioligand is displaced) and pKi (negative logarithm of the molar concentration of the Ki ) values of individual antimigraine drugs at 5‐HT receptors [...] TABLE 2 Summary of pEC50 values of cAMP (5‐HT1A/B/E/F and 5‐HT7), GTPγS (5‐HT1A/B/D/E/F), and IP (5‐HT2) assays of individual antimigraine drugs at 5‐HT receptors [...]". 
  19. ↑ Perez, M.; Halazy, S.; Pauwels, P.J.; Colpaert, F.C.; John, G.W. (1999). "F-11356". Drugs of the Future 24 (6): 0605. doi:10.1358/dof.1999.024.06.537284. http://access.portico.org/stable?au=pjbf78x6c9d. Retrieved 23 June 2025. 
  20. ↑ "Lasmiditan hydrochloride". Drugs of the Future 37 (10): 709. 2012. doi:10.1358/dof.2012.037.010.1873629. ISSN 0377-8282. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1873629&p_IsPs=N. Retrieved 19 June 2025. 
  21. ↑ "Evidence-based symptomatic treatment of migraine". Migraine Management. Handbook of Clinical Neurology. 199. 2024. pp. 203–218. doi:10.1016/B978-0-12-823357-3.00004-5. ISBN 978-0-12-823357-3. 
  22. ↑ "Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan". Headache 42 (Suppl 2): S47–S53. April 2002. doi:10.1046/j.1526-4610.42.s2.2.x. PMID 12028320. 
  23. ↑ "Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy". Naunyn Schmiedebergs Arch Pharmacol 355 (6): 682–688. June 1997. doi:10.1007/pl00005000. PMID 9205951. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 "Naratriptan". https://pubchem.ncbi.nlm.nih.gov/compound/4440. 
  25. ↑ "Medicinal chemistry of antimigraine drugs". Curr Med Chem 20 (26): 3300–3316. 2013. doi:10.2174/0929867311320260012. PMID 23746273. 
  26. ↑ "Naratriptan: Uses, Interactions, Mechanism of Action". 5 May 1998. https://go.drugbank.com/drugs/DB00952. 
  27. ↑ 27.0 27.1 "Naratriptan Hydrochloride". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020763&TABLE1=OB_Rx. 
  28. ↑ Oxford AW, Sutina D, Owen MR, "Indole derivatives", US patent 4997841, issued 5 March 1991, assigned to Glaxo Group Ltd
  29. ↑ "Roxane launches generic Amerge, Arimidex". Drug Store News. 2010-07-09. https://drugstorenews.com/pharmacy/roxane-launches-generic-amerge-arimidex. 
  30. ↑ "Sandoz launches generic Amerge". Drug Store News. 2010-07-12. https://drugstorenews.com/pharmacy/sandoz-launches-generic-amerge. 
  31. ↑ "Teva launches generic Amerge". Drug Store News. 2010-07-14. https://drugstorenews.com/pharmacy/teva-launches-generic-amerge. 
  32. ↑ 32.0 32.1 32.2 "Drug In Focus: Naratriptan". GenericsWeb. June 2010. http://www.genericsweb.com/druginfocus/Naratriptan_press_release. 
  33. ↑ "Health products quarantined from two India sites". Government of Canada. December 24, 2014. http://www.hc-sc.gc.ca/dhp-mps/compli-conform/info-prod/drugs-drogues/advisory-avis-drreddys_ipca-eng.php. 
  34. ↑ "Health products quarantined from two sites in India as Health Canada assesses data integrity concerns". Health Canada. December 23, 2014. http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/43061a-eng.php. 
  35. ↑ 35.0 35.1 "Dr. Reddy's largest API Facility Maybe the Next to Get Banned from Exporting to the United States" (in en-gb). PharmaCompass (LePro PharmaCompass OPC Private Limited). March 30, 2015. https://www.pharmacompass.com/radio-compass-blog/dr-reddy-s-largest-api-facility-maybe-the-next-to-get-banned-from-exporting-to-the-united-states. 
  36. ↑ "Stop the importation and distribution of Medical Products manufactured by Dr. Reddy's Laboratories in Srikakulam, India & IPCA Laboratories in Pithampur". Health Authority – Abu Dhabi (HAAD). United Arab Emirates Ministry of Health. 19 February 2015. https://www.haad.ae/HAAD/LinkClick.aspx?fileticket=KDlNvA7PC0s%3d&tabid=207. 



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