Naratriptan

Last updated

Naratriptan
Naratriptan.svg
Naratriptan 3D ball-and-stick.png
Clinical data
Trade names Amerge, Naramig, others
Other namesGR-85548; GR85548; GR-85548A; GR85548A; SMP-948; SMP948
AHFS/Drugs.com Monograph
MedlinePlus a601083
Pregnancy
category
  • AU:B3
Routes of
administration 		Oral
Drug class Serotonin 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
Bioavailability 74%
Metabolism Hepatic
Elimination half-life 5–8 hours
Excretion Renal
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 InfoCard 100.121.501 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H25N3O2S
Molar mass 335.47 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 Yes check.svgY
  • Key:AMKVXSZCKVJAGH-UHFFFAOYSA-N Yes check.svgY
   (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.

Contents

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 Tooltip half-maximal effective concentration)
65–79% (Emax Tooltip 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
TAAR1 Tooltip Trace amine-associated receptor 1ND
SERT Tooltip Serotonin transporterND
NET Tooltip Norepinephrine transporterND
DAT Tooltip Dopamine transporterND
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 ethyl amine 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 2 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. 1 2 3 4 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. ↑ Newman-Tancredi A, Conte C, Chaput C, Verrièle L, Audinot-Bouchez V, Lochon S, Lavielle G, Millan MJ (June 1997). "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. doi:10.1007/pl00005000. PMID   9205951.
  24. 1 2 3 4 5 "Naratriptan". PubChem. Retrieved 27 June 2025.
  25. ↑ 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.
  26. ↑ "Naratriptan: Uses, Interactions, Mechanism of Action". DrugBank Online. 5 May 1998. Retrieved 27 June 2025.
  27. 1 2 "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.
  28. ↑ US 4997841,Oxford AW, Sutina D, Owen MR,"Indole derivatives",issued 5 March 1991, assigned to Glaxo Group Ltd
  29. ↑ DeArment A (2010-07-09). "Roxane launches generic Amerge, Arimidex". Drug Store News. Retrieved 2010-07-23.
  30. ↑ DeArment A (2010-07-12). "Sandoz launches generic Amerge". Drug Store News. Retrieved 2010-07-23.
  31. ↑ DeArment A (2010-07-14). "Teva launches generic Amerge". Drug Store News. Retrieved 2010-07-23.
  32. 1 2 3 Oh D (June 2010). "Drug In Focus: Naratriptan". GenericsWeb. Archived from the original on 2017-01-06. Retrieved 2010-12-15.
  33. ↑ "Health products quarantined from two India sites". Health Canada. Government of Canada. December 24, 2014. Retrieved September 14, 2017.
  34. ↑ "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.
  35. 1 2 "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.
  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). 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.
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