Chemistry:Eletriptan

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Eletriptan, sold under the brand name Relpax and used in the form of eletriptan hydrobromide, is a second-generation triptan medication intended for treatment of migraine headaches.[1][2][3] It is used as an abortive medication, blocking a migraine attack which is already in progress.[1] Eletriptan is marketed and manufactured by Pfizer.[1]

Eletriptan is a therapeutic alternative on the World Health Organization's List of Essential Medicines.[4]

Medical uses

Eletriptan was approved by the United States Food and Drug Administration (FDA) in December 2002, for the acute treatment of migraine with or without aura in adults.[5][1] It is available only by prescription in the United States, Canada, and Australia. It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine.[1] It is available in 20 mg and 40 mg strengths.[1]

Contraindications

Eletriptan is contraindicated in patients with various diseases of the heart and circulatory system, such as angina pectoris, severe hypertension, and heart failure, as well as in patients that have had a stroke or heart attack.[1] This is due to the unusual side effect of coronary vasoconstriction due to serotonin 5-HT1B receptor agonism, which can precipitate a heart attack in those already at risk.[1] It is also contraindicated in severe kidney (renal) or liver (hepatic) impairment due to its extensive liver metabolism through CYP3A4.[6][1]

Side effects

Common side effects include hypertension, tachycardia, headache, dizziness, drowsiness, and symptoms similar to angina pectoris.[1] Severe allergic reactions have been seen rarely.[6][1]

Interactions

Strong inhibitors of the liver enzyme CYP3A4, such as erythromycin and ketoconazole, significantly increase blood plasma concentration of eletriptan and should be separated by at least 72 hours.[1] Ergot alkaloids, such as dihydroergotamine, add to the drug's hypertensive effect and should be separated by at least 24 hours.[6][1]

Pharmacology

Mechanism of action

Eletriptan activities
Target Affinity (Ki, nM)
5-HT1A 1.9–45 (Ki)
417–1,820 (EC50)
5-HT1B 0.52–15.1 (Ki)
8.1–60 (EC50)
83% (Emax)
5-HT1D 0.10–1.5 (Ki)
0.63–0.91 (EC50)
5-HT1E 40–62 (Ki)
30–126 (EC50)
5-HT1F 5–20 (Ki)
7.4–132 (EC50)
5-HT2A 1,150–>3,160 (Ki)
851 (EC50)
5-HT2B 447 (Ki)
155 (EC50)
5-HT2C >3,160 (Ki)
ND (EC50)
5-HT3 >3,160 (mouse)
5-HT4 >3,160 (guinea pig)
5-HT5A 977–1,584 (rat)
5-HT6 525
5-HT7 200 (Ki)
355 (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: [7][8][9][10][11][12][13][14]
[15][16][17][18]

Eletriptan is believed to reduce swelling of the blood vessels surrounding the brain. This swelling is associated with the head pain of a migraine attack. Eletriptan blocks the release of substances from nerve endings that cause more pain and other symptoms like nausea, and sensitivity to light and sound. It is thought that these actions contribute to relief of symptoms by eletriptan.

Eletriptan is a serotonin receptor agonist, specifically an agonist of certain 5-HT1 family receptors.[1] Eletriptan binds with high affinity to the 5-HT[1B, 1D, 1F] receptors. It has a modest affinity to the 5-HT[1A, 1E, 2B, 7] receptors, and little to no affinity at the 5-HT[2A, 2C, 3, 4, 5A, 6] receptors.

Eletriptan has no significant affinity or pharmacological activity at adrenergic α1, α2, or β; dopaminergic D1 or D2; muscarinic; or opioid receptors. Eletriptan could be efficiently co-administered with nitric oxide synthase (NOS's) inhibitors for the treatment of NOS-dependent diseases (US patent US 2007/0254940).

Two theories have been proposed to explain the efficacy of 5-HT1 receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

The drug is also notable in being a weak serotonin 5-HT2A receptor agonist (EC50 = 851 nM), albeit with about two to three orders of magnitude lower activational potency than at the serotonin 5-HT1B and 5-HT1D receptors.[15]

Chemistry

Eletriptan is a tryptamine and pyrrolidinylmethylindole derivative and is a 5-substituted and cyclized tryptamine derivative of the psychedelic drug dimethyltryptamine (DMT).[19]

The experimental log P is 3.9 and its predicted log P is 1.78 to 4.1.[20][19][21]

Additional chemical names

  • Merck Index: 3-[[(2R)-1-Methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole
  • 5-[2-(benzenesulfonyl)ethyl]-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole
  • (R)-5-[2-(phenylsulfonyl)ethyl]-3-[(1-methyl-2-pyrrolidinyl)methyl]-1H-indole

History

Eletriptan was approved for medical use in the United States in 2002.[1] It was covered by U.S. Patent no. 5545644[5][22] and U.S. Patent no. 6110940;[5][23] both now expired.

Society and culture

Brand names

Eletriptan is sold in the United States, Canada, Australia, and the United Kingdom under the brand name Relpax,[1][24][25] and in several other countries under the brand name Relert.[citation needed]

In the United States, Relpax is marketed by Viatris after Upjohn was spun off from Pfizer.[26][27][28]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Cite error: Invalid <ref> tag; no text was provided for refs named Relpax FDA label
  2. ↑ "A review of the pharmacoeconomics of eletriptan for the acute treatment of migraine". International Journal of General Medicine 8: 27–36. 2015. doi:10.2147/IJGM.S73673. PMID 25624770. 
  3. ↑ "Eletriptan in the management of acute migraine: an update on the evidence for efficacy, safety, and consistent response". Therapeutic Advances in Neurological Disorders 9 (5): 414–23. September 2016. doi:10.1177/1756285616650619. PMID 27582896. 
  4. ↑ The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list. Geneva: World Health Organization. 2025. doi:10.2471/B09474. 
  5. ↑ 5.0 5.1 5.2 "Drug Approval Package: Relpax (Eletriptan) NDA #021016". 4 April 2002. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21016_Relpax.cfm. 
  6. ↑ 6.0 6.1 6.2 (in German) Austria-Codex (62nd ed.). Vienna: Österreichischer Apothekerverlag. 2007. pp. 6984–8. ISBN 978-3-85200-181-4. 
  7. ↑ Liu, Tiqing. "BDBM50103594 CHEBI:50922::Eletriptan::UK-116044::UK-116044-04::UK-116044-04 [As Hydrobromide)". https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50103594. 
  8. ↑ "Pharmacology of triptans". Emerging Drugs 4 (1): 107–125. 1999. doi:10.1517/14728214.4.1.107. ISSN 1361-9195. 
  9. ↑ "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. 
  10. ↑ "Success and failure of triptans". The Journal of Headache and Pain 2 (1): 3–11. 2001. doi:10.1007/s101940170040. ISSN 1129-2369. 
  11. ↑ "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. [...]" 
  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. ↑ "Migraine headache treatment with eletriptan, a second-generation serotonin receptor agonist". Drugs Today (Barc) 37 (3): 159–171. March 2001. doi:10.1358/dot.2001.37.3.614851. PMID 12783088. 
  14. ↑ "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. [...]" 
  15. ↑ 15.0 15.1 "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 [...]". 
  16. ↑ 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. 
  17. ↑ "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. 
  18. ↑ "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. 
  19. ↑ 19.0 19.1 "Eletriptan". https://pubchem.ncbi.nlm.nih.gov/compound/77993. 
  20. ↑ "Medicinal chemistry of antimigraine drugs". Curr Med Chem 20 (26): 3300–3316. 2013. doi:10.2174/0929867311320260012. PMID 23746273. 
  21. ↑ "Eletriptan: Uses, Interactions, Mechanism of Action". 31 July 2019. https://go.drugbank.com/drugs/DB00216. 
  22. ↑ U.S. Patent no. 5545644, John E. Macor & Martin J. Wythes, Indole Derivatives, 13 August 1996.
  23. ↑ U.S. Patent no. 6110940, Valerie Denise Harding, et al., Salts of an anti-migraine indole derivative, 29 August 2000.
  24. ↑ "Relpax Product information". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=74152. 
  25. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Relpax SmPC
  26. ↑ "Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan". Pfizer. 16 November 2020. https://www.businesswire.com/news/home/20201116005378/en/. 
  27. ↑ "Relpax". https://www.pfizer.com/products/product-detail/relpax. 
  28. ↑ "Brands". 16 November 2020. https://www.viatris.com/en/products/brands. 



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