Chemistry:Donitriptan

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Donitriptan (INN; developmental code name F-11356) is a triptan drug which was investigated as an antimigraine agent but was never marketed.[1][2][3] It acts as a selective serotonin 5-HT1B and 5-HT1D receptor agonist.[4][5][6][3] The drug reached phase 2 clinical trials prior to the discontinuation of its development.[7]

Pharmacology

Donitriptan activities
Target Affinity (Ki, nM)
5-HT1A 12–25 (Ki)
182–1,150 (EC50)
5-HT1B 0.08–0.36 (Ki)
0.10–1.8 (EC50)
94–100% (Emax)
5-HT1D 0.06–0.48 (Ki)
0.27–0.83 (EC50)
97–99% (Emax)
5-HT1E 1,150–1,700 (Ki)
>10,000 (EC50)
5-HT1F 3,390–6,610 (Ki)
>10,000 (EC50)
5-HT2A 182–447 (Ki)
7.9 (EC50)
5-HT2B 813 (Ki)
25 (EC50)
5-HT2C 575 (Ki) (rat)
ND (EC50)
5-HT3 >10,000 (mouse)
5-HT4 2,000 (guinea pig)
5-HT5A 813
5-HT6 2,340
5-HT7 372–617 (Ki)
5,890 (EC50)
α1A–α1D ND
α2A–α2C ND
β1–β3 ND
D1 >10,000
D2 >10,000
D3–D5 ND
H1 >10,000
H2 >10,000
H3, H4 ND
M1–M5 ND
mACh >10,000
I1, I2 >1,000
σ1, σ2 ND
TAAR1 ND
SERT >1,000 (IC50)
NET >1,000 (IC50)
DAT >1,000 (IC50)
MAO-A >10,000
MAO-B >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][8][9][6][3]

Donitriptan acts as a high-affinity, high-efficacy near-full agonist of the serotonin 5-HT1B (Ki = 0.079–0.40 nM; Emax = 94%) and 5-HT1D receptors (Ki = 0.063–0.50 nM; Emax = 97%), and is among the most potent of the triptan series of drugs.[3][10][11][4] It is also notable and unique among most of the triptans in being a potent serotonin 5-HT2A receptor agonist (EC50 = 7.9 nM), albeit with about one or two orders of magnitude lower activational potency than at the serotonin 5-HT1B and 5-HT1D receptors.[6]

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.[12]

The predicted log P of donitriptan is 1.32 to 2.2.[12][13]

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.[14][15][16][3]

See also

References

  1. ↑ "Donitriptan". 22 May 2000. https://adisinsight.springer.com/drugs/800010652. 
  2. ↑ "Donitriptan (Pierre Fabre)". Current Opinion in Investigational Drugs 2 (3): 415–418. March 2001. PMID 11575714. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 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. 
  4. ↑ 4.0 4.1 4.2 "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. doi:10.1016/S0022-3565(24)34871-2. PMID 10381763. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=b87c5aaccd3f3bddf0403e949a2c435bf6e0e2eb. 
  5. ↑ 5.0 5.1 "Pharmacology of triptans". Emerging Drugs 4 (1): 107–125. 1999. doi:10.1517/14728214.4.1.107. ISSN 1361-9195. 
  6. ↑ 6.0 6.1 6.2 "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 [...]". 
  7. ↑ "Delving into the Latest Updates on Donitriptan Mesylate with Synapse". 19 July 2025. https://synapse.patsnap.com/drug/e3bbd23dc5cb4cb88224b774d30a3ca4. 
  8. ↑ "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. [...]" 
  9. ↑ "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. [...]" 
  10. ↑ "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. doi:10.1021/jm00018a020. PMID 7658447. 
  11. ↑ "Triptans, 5-HT1B/1D Receptor Agonists in the Acute Treatment of Migraine". The Headaches. Lippincott Williams & Wilkins. 2006. pp. 470–. ISBN 978-0-7817-5400-2. https://books.google.com/books?id=VXMI1ry9FgQC&pg=PA470. 
  12. ↑ 12.0 12.1 "Donitriptan". https://pubchem.ncbi.nlm.nih.gov/compound/197706. 
  13. ↑ "donitriptan". 10 June 2024. https://www.chemspider.com/Chemical-Structure.171128.html. 
  14. ↑ "An Overview of Current and Investigational Drugs for the Treatment of Acute and Chronic Pain". Pain: Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery. CRC Press. 28 May 2013. pp. 402–. ISBN 978-0-203-91125-9. https://books.google.com/books?id=anRzslvfcUwC&pg=PA402. 
  15. ↑ Neuropsychopharmacology. Springer Vienna. 21 May 2003. pp. 38–. ISBN 978-3-211-83903-4. https://books.google.com/books?id=1ySUGaXI_wEC&pg=PA38. 
  16. ↑ "New Areas of Research". Understanding Migraine and Other Headaches. Univ. Press of Mississippi. 2004. pp. 118. ISBN 978-1-60473-048-7. https://archive.org/details/understandingmig00stew. 



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