Naratriptan

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Naratriptan
Clinical data
Trade namesAmerge, Naramig, others
Other namesGR-85548; GR85548; GR-85548A; GR85548A; SMP-948; SMP948
AHFS/Drugs.comMonograph
MedlinePlusa601083
Pregnancy
category
  • AU: B3
Routes of
administration		Oral
Drug classSerotonin 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor agonist; Antimigraine agent; Triptan
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability74%
MetabolismHepatic
Elimination half-life5–8 hours
ExcretionRenal
Identifiers
  • N-methyl-2-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.121.501 Edit this at Wikidata
Chemical and physical data
FormulaC17H25N3O2S
Molar mass335.47 g·mol−1
3D model (JSmol)
  • O=S(=O)(NC)CCc3ccc1c(c(c[nH]1)C2CCN(C)CC2)c3
  • InChI=1S/C17H25N3O2S/c1-18-23(21,22)10-7-13-3-4-17-15(11-13)16(12-19-17)14-5-8-20(2)9-6-14/h3-4,11-12,14,18-19H,5-10H2,1-2H3 checkY
  • Key:AMKVXSZCKVJAGH-UHFFFAOYSA-N checkY
  (verify)

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

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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

[edit]

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

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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

[edit]

Mechanism of action

[edit]
Further information: Serotonin receptor agonist and Triptan § Mechanism of action
Naratriptan activities
Target Affinity (Ki, nM)
5-HT1A 15–79 (Ki)
302–>10,000 (EC50Tooltip half-maximal effective concentration)
65% (EmaxTooltip maximal efficacy)
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
TAAR1Tooltip Trace amine-associated receptor 1 ND
SERTTooltip Serotonin transporter ND
NETTooltip Norepinephrine transporter ND
DATTooltip Dopamine transporter 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]

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

[edit]

Naratriptan is a triptan and a modified analogue of tryptamines like the psychedelic drug dimethyltryptamine (DMT).[23] 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.[23] Besides this difference, naratriptan is substituted at the 5 position of the indole ring system and the amine moiety has been cyclized.[23] Instead of being a tryptamine, naratriptan is a piperidinylindole.[23]

The experimental log P of naratriptan is 1.6 to 2.16 and its predicted log P is 0.28 to 2.16.[24][23][25]

History

[edit]

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

Society and culture

[edit]

In the United States, the Food and Drug Administration (FDA) approved naratriptan on February 11, 1998.[26] It was covered by U.S. Patent no. 4997841; the FDA lists the patent as expiring on July 7, 2010.[26][27]

In July 2010, in the wake of the patent expiration, several drug manufacturers, including Roxane Labs,[28] Sandoz[29] and Teva Pharmaceuticals,[30] 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,[31] and by Australian patent 611469 in Australia through June 17, 2013.[31] 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.[31]

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.[32][33] 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.[34]

Following the Canadian quarantine, the United Arab Emirates' Ministry of Health also imposed a similar quarantine.[34][35]

See also

[edit]

References

[edit]
  1. ^ a b Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 531. ISBN 978-3-527-60749-5.
  2. ^ "Naratriptan". Medline Plus Drug Information. U.S. National Library of Medicine. Retrieved 6 August 2009.
  3. ^ Ferrari MD, Goadsby PJ, Roon KI, Lipton RB (October 2002). "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. doi:10.1046/j.1468-2982.2002.00404.x. PMID 12383060. S2CID 2368571.
  4. ^ Havanka H, Dahlöf C, Pop PH, Diener HC, Winter P, Whitehouse H, et al. (S2WB2004 Study Group) (August 2000). "Efficacy of naratriptan tablets in the acute treatment of migraine: a dose-ranging study". Clinical Therapeutics. 22 (8): 970–80. 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. S2CID 219185675.
  6. ^ a b c d Mathew NT (May 1999). "Naratriptan: a review". Expert Opinion on Investigational Drugs. 8 (5): 687–695. doi:10.1517/13543784.8.5.687. ISSN 1354-3784. PMID 15992123.
  7. ^ Pascual J, Mateos V, Roig C, Sanchez-Del-Rio M, Jiménez D (2007). "Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability". Headache. 47 (8): 1152–68. doi:10.1111/j.1526-4610.2007.00849.x. PMID 17883520.
  8. ^ "Kᵢ Database". PDSP. 19 July 2025. Retrieved 19 July 2025.
  9. ^ Liu T. "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". BindingDB. Retrieved 19 July 2025.
  10. ^ De Vries P, Villalón CM, Saxena PR (1999). "Pharmacology of triptans". Emerging Drugs. 4 (1): 107–125. doi:10.1517/14728214.4.1.107. ISSN 1361-9195.
  11. ^ Tfelt-Hansen P, De Vries P, Saxena PR (December 2000). "Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy". Drugs. 60 (6): 1259–1287. doi:10.2165/00003495-200060060-00003. PMID 11152011.
  12. ^ Deleu D, Hanssens Y (July 2000). "Current and emerging second-generation triptans in acute migraine therapy: a comparative review". J Clin Pharmacol. 40 (7): 687–700. doi:10.1177/00912700022009431. PMID 10883409.
  13. ^ Saxena PR, Tfelt-Hansen P (2001). "Success and failure of triptans". The Journal of Headache and Pain. 2 (1): 3–11. doi:10.1007/s101940170040. ISSN 1129-2369. PMC 3611827.
  14. ^ van den Brink M (22 December 1999). "Coronary Side Effects of Antimigraine Drugs From Patient to Receptor". RePub, Erasmus University Repository. Retrieved 19 June 2025. Table 1.2 Receptor binding properties (pKi values) of sumatriptan and second-generation triptans at 5-HT receptors. [...]
  15. ^ van den Broek RW (13 March 2002). "Vascular Effects of Antimigraine Drugs: pharmacology of human in vitro models in migraine". RePub, Erasmus University Repository. Retrieved 19 June 2025. Table 1.2 Receptor binding properties (pKi values) of the triptans at human 5-HT receptors. [...]
  16. ^ Pauwels PJ, Tardif S, Palmier C, Wurch T, Colpaert FC (1997). "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. doi:10.1016/s0028-3908(96)00170-0. PMID 9225275.
  17. ^ Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, Xu YC (October 2010). "Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan". Cephalalgia. 30 (10): 1159–1169. doi:10.1177/0333102410370873. PMID 20855361.
  18. ^ Rubio-Beltrán E, Labastida-Ramírez A, Haanes KA, van den Bogaerdt A, Bogers AJ, Zanelli E, Meeus L, Danser AH, Gralinski MR, Senese PB, Johnson KW, Kovalchin J, Villalón CM, MaassenVanDenBrink A (December 2019). "Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan". British Journal of Pharmacology. 176 (24): 4681–4695. doi:10.1111/bph.14832. PMC 6965684. 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. Retrieved 23 June 2025.
  20. ^ Reuter U, Neeb L (2012). "Lasmiditan hydrochloride". Drugs of the Future. 37 (10): 709. doi:10.1358/dof.2012.037.010.1873629. ISSN 0377-8282. Retrieved 19 June 2025.
  21. ^ Mitsikostas DD, Ward TN (2024). "Evidence-based symptomatic treatment of migraine". Migraine Management. Handbook of Clinical Neurology. Vol. 199. pp. 203–218. doi:10.1016/B978-0-12-823357-3.00004-5. ISBN 978-0-12-823357-3. PMID 38307647.
  22. ^ Comer MB (April 2002). "Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan". Headache. 42 (Suppl 2): S47 – S53. doi:10.1046/j.1526-4610.42.s2.2.x. PMID 12028320.
  23. ^ a b c d e "Naratriptan". PubChem. Retrieved 27 June 2025.
  24. ^ Tekes K, Szegi P, Hashemi F, Laufer R, Kalász H, Siddiq A, Ertsey C (2013). "Medicinal chemistry of antimigraine drugs". Curr Med Chem. 20 (26): 3300–3316. doi:10.2174/0929867311320260012. PMID 23746273.
  25. ^ "Naratriptan: Uses, Interactions, Mechanism of Action". DrugBank Online. 5 May 1998. Retrieved 27 June 2025.
  26. ^ a b "Naratriptan Hydrochloride". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. Archived from the original on 3 March 2016. Retrieved 8 September 2008.
  27. ^ US 4997841, Oxford AW, Sutina D, Owen MR, "Indole derivatives", issued 5 March 1991, assigned to Glaxo Group Ltd 
  28. ^ DeArment A (2010-07-09). "Roxane launches generic Amerge, Arimidex". Drug Store News. Retrieved 2010-07-23.
  29. ^ DeArment A (2010-07-12). "Sandoz launches generic Amerge". Drug Store News. Retrieved 2010-07-23.
  30. ^ DeArment A (2010-07-14). "Teva launches generic Amerge". Drug Store News. Retrieved 2010-07-23.
  31. ^ a b c Oh D (June 2010). "Drug In Focus: Naratriptan". GenericsWeb. Archived from the original on 2017-01-06. Retrieved 2010-12-15.
  32. ^ "Health products quarantined from two India sites". Health Canada. Government of Canada. December 24, 2014. Retrieved September 14, 2017.
  33. ^ "Health products quarantined from two sites in India as Health Canada assesses data integrity concerns". Recalls and safety alerts. Health Canada. December 23, 2014. Retrieved September 14, 2017.
  34. ^ a b "Dr. Reddy's largest API Facility Maybe the Next to Get Banned from Exporting to the United States". PharmaCompass. LePro PharmaCompass OPC Private Limited. March 30, 2015. Retrieved September 14, 2017.
  35. ^ "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). Circular no. HRD/017/15. United Arab Emirates Ministry of Health. 19 February 2015. Archived from the original on 15 September 2017. Retrieved 14 September 2017.