Donitriptan Explained

Donitriptan (; developmental code name F-11356) is a triptan drug which was investigated as an antimigraine agent but was never marketed.[1] [2] It acts as a selective serotonin 5-HT1B and 5-HT1D receptor agonist. The drug reached phase 2 clinical trials prior to the discontinuation of its development.[3]

Pharmacology

Affinity (Ki, nM)
12–25 (Ki)
182–1,150
0.08–0.36 (Ki)
0.10–1.8
94–100%
0.06–0.48 (Ki)
0.27–0.83
97–99%
1,150–1,700 (Ki)
3,390–6,610 (Ki)
182–447 (Ki)
7.9
813 (Ki)
25
575 (Ki) (rat)
>10,000 (mouse)
2,000 (guinea pig)
813
2,340
372–617 (Ki)
5,890
>10,000
>10,000
>10,000
>10,000
>10,000
>1,000
>1,000
>1,000
>1,000
>10,000
>10,000
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [4] [5] [6] [7] [8] [9]

Donitriptan acts as a high-affinity, high-efficacy near-full agonist of the serotonin 5-HT1B (Ki = 0.079–0.40nM; = 94%) and 5-HT1D receptors (Ki = 0.063–0.50nM; = 97%), and is among the most potent of the triptan series of drugs.[10] [11] It is also notable and unique among most of the triptans in being a potent serotonin 5-HT2A receptor agonist (= 7.9nM), albeit with about one or two orders of magnitude lower activational potency than at the serotonin 5-HT1B and 5-HT1D receptors.[12]

Chemistry

Donitriptan is a tryptamine derivative, a 5-substituted derivative of tryptamine and 5-methoxytryptamine, and an analogue of the psychedelic drugs dimethyltryptamine (DMT) and 5-MeO-DMT.

The predicted log P of donitriptan is 1.32 to 2.2.[13] [14]

History

Donitriptan was being developed in France by bioMérieux-Pierre Fabre and made it to phase II clinical trials in Europe before development was discontinued.[15] [16] [17]

See also

Notes and References

  1. Web site: Donitriptan . AdisInsight . 22 May 2000 . 29 July 2025.
  2. Dukat M . Donitriptan (Pierre Fabre) . Current Opinion in Investigational Drugs . 2 . 3 . 415–418 . March 2001 . 11575714 .
  3. Web site: Delving into the Latest Updates on Donitriptan Mesylate with Synapse . Synapse . 19 July 2025 . 29 July 2025.
  4. John GW, Pauwels PJ, Perez M, Halazy S, Le Grand B, Verscheure Y, Valentin JP, Palmier C, Wurch T, Chopin P, Marien M, Kleven MS, Koek W, Assie MB, Carilla-Durand E, Tarayre JP, Colpaert FC . F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine . J Pharmacol Exp Ther . 290 . 1 . 83–95 . July 1999 . 10381763 . 10.1016/S0022-3565(24)34871-2. subscription .
  5. De Vries P, Villalón CM, Saxena PR . Pharmacology of triptans . Emerging Drugs . 4 . 1 . 1999 . 1361-9195 . 10.1517/14728214.4.1.107 . 107–125 .
  6. Web site: van den Brink M . Coronary Side Effects of Antimigraine Drugs From Patient to Receptor . RePub, Erasmus University Repository . 22 December 1999 . 19 June 2025 . Table 1.2 Receptor binding properties (pKi values) of sumatriptan and second-generation triptans at 5-HT receptors. [...].
  7. Web site: van den Broek RW . Vascular Effects of Antimigraine Drugs: pharmacology of human in vitro models in migraine . RePub, Erasmus University Repository . 13 March 2002 . 19 June 2025 . Table 1.2 Receptor binding properties (pKi values) of the triptans at human 5-HT receptors. [...].
  8. 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 . 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 . 31418454 . 6965684 . 10.1111/bph.14832 . 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 [...] .
  9. Perez, M. . Halazy, S. . Pauwels, P.J. . Colpaert, F.C. . John, G.W. . F-11356 . Drugs of the Future . 24 . 6 . 1999 . 10.1358/dof.1999.024.06.537284 . 0605 . 23 June 2025. subscription .
  10. Perez M, Fourrier C, Sigogneau I, Pauwels PJ, Palmier C, John GW, Valentin JP, Halazy S . 6 . Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors . Journal of Medicinal Chemistry . 38 . 18 . 3602–3607 . September 1995 . 7658447 . 10.1021/jm00018a020 .
  11. Book: Saxena PR, Tfelt-Hansen P . Triptans, 5-HT1B/1D Receptor Agonists in the Acute Treatment of Migraine. Olesen J . The Headaches. https://books.google.com/books?id=VXMI1ry9FgQC&pg=PA470. 2006. Lippincott Williams & Wilkins. 978-0-7817-5400-2. 470–.
  12. 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 . 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 . 31418454 . 6965684 . 10.1111/bph.14832 . 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 [...] .
  13. Web site: Donitriptan . PubChem . 24 June 2025.
  14. Web site: donitriptan . ChemSpider . 10 June 2024 . 24 June 2025.
  15. Book: Schmidt WK . An Overview of Current and Investigational Drugs for the Treatment of Acute and Chronic Pain . Bountra C, Munglani R, Schmidt WK . Pain: Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery. https://books.google.com/books?id=anRzslvfcUwC&pg=PA402. 28 May 2013. CRC Press. 978-0-203-91125-9. 402–.
  16. Book: Fleischhacker WW, Brooks DJ . Neuropsychopharmacology. 21 May 2003. Springer Vienna. 978-3-211-83903-4. 38–.
  17. Book: Tepper SJ . New Areas of Research . Understanding Migraine and Other Headaches. https://archive.org/details/understandingmig00stew . 2004. Univ. Press of Mississippi. 118 . 978-1-60473-048-7 .

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