Donitriptan

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Donitriptan
Clinical data
Other namesF-11356; F11356; F-12640; F12640
Drug classSerotonin 5-HT1B and 5-HT1D receptor agonist; Antimigraine agent; Triptan
ATC code
  • None
Legal status
Legal status
  • Never marketed
Identifiers
  • 4-[4-({[3-(2-Aminoethyl)-1H-indol-5-yl]oxy}acetyl)-1-piperazinyl]benzonitrile
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H25N5O2
Molar mass403.486 g·mol−1
3D model (JSmol)
  • c1cc(ccc1C#N)N2CCN(CC2)C(=O)COc3ccc4c(c3)c(c[nH]4)CCN
  • InChI=1S/C23H25N5O2/c24-8-7-18-15-26-22-6-5-20(13-21(18)22)30-16-23(29)28-11-9-27(10-12-28)19-3-1-17(14-25)2-4-19/h1-6,13,15,26H,7-12,16,24H2
  • Key:SOHCKWZVTCTQBG-UHFFFAOYSA-N

Donitriptan (INNTooltip International Nonproprietary Name; 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

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Donitriptan activities
Target Affinity (Ki, nM)
5-HT1A 12–25 (Ki)
182–1,150 (EC50Tooltip half-maximal effective concentration)
5-HT1B 0.08–0.36 (Ki)
0.10–1.8 (EC50)
94–100% (EmaxTooltip maximal efficacy)
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
TAAR1Tooltip Trace amine-associated receptor 1 ND
SERTTooltip Serotonin transporter >1,000 (IC50Tooltip half-maximal inhibitory concentration)
NETTooltip Norepinephrine transporter >1,000 (IC50)
DATTooltip Dopamine transporter >1,000 (IC50)
MAO-ATooltip Monoamine oxidase A >10,000
MAO-BTooltip Monoamine oxidase 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; EmaxTooltip maximal efficacy = 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 (EC50Tooltip half-maximal effective concentration = 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

[edit]

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

[edit]

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

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References

[edit]
  1. ^ "Donitriptan". AdisInsight. 22 May 2000. Retrieved 29 July 2025.
  2. ^ Dukat M (March 2001). "Donitriptan (Pierre Fabre)". Current Opinion in Investigational Drugs. 2 (3): 415–418. PMID 11575714.
  3. ^ a b c d e 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.
  4. ^ a b c 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 (July 1999). "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. PMID 10381763.
  5. ^ a b 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.
  6. ^ a b c 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 [...]
  7. ^ "Delving into the Latest Updates on Donitriptan Mesylate with Synapse". Synapse. 19 July 2025. Retrieved 29 July 2025.
  8. ^ 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. [...]
  9. ^ 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. [...]
  10. ^ Perez M, Fourrier C, Sigogneau I, Pauwels PJ, Palmier C, John GW, et al. (September 1995). "Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors". Journal of Medicinal Chemistry. 38 (18): 3602–3607. doi:10.1021/jm00018a020. PMID 7658447.
  11. ^ Saxena PR, Tfelt-Hansen P (2006). "Triptans, 5-HT1B/1D Receptor Agonists in the Acute Treatment of Migraine". In Olesen J (ed.). The Headaches. Lippincott Williams & Wilkins. pp. 470–. ISBN 978-0-7817-5400-2.
  12. ^ a b "Donitriptan". PubChem. Retrieved 24 June 2025.
  13. ^ "donitriptan". ChemSpider. 10 June 2024. Retrieved 24 June 2025.
  14. ^ Schmidt WK (28 May 2013). "An Overview of Current and Investigational Drugs for the Treatment of Acute and Chronic Pain". In Bountra C, Munglani R, Schmidt WK (eds.). Pain: Current Understanding, Emerging Therapies, and Novel Approaches to Drug Discovery. CRC Press. pp. 402–. ISBN 978-0-203-91125-9.
  15. ^ Fleischhacker WW, Brooks DJ (21 May 2003). Neuropsychopharmacology. Springer Vienna. pp. 38–. ISBN 978-3-211-83903-4.
  16. ^ Tepper SJ (2004). "New Areas of Research". Understanding Migraine and Other Headaches. Univ. Press of Mississippi. pp. 118. ISBN 978-1-60473-048-7.