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Donitriptan

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
Donitriptan
Clinical data
Other namesF-11356; F11356; F-12640; F12640
Drug classSerotonin5-HT1B and5-HT1D receptoragonist;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
PubChemCID
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 nameF-11356) is atriptandrug which was investigated as anantimigraine agent but was never marketed.[1][2][3] It acts as aselectiveserotonin5-HT1B and5-HT1D receptoragonist.[4][5][6][3] The drug reachedphase 2clinical trials prior to the discontinuation of its development.[7]

Pharmacology

[edit]
Donitriptan activities
TargetAffinity (Ki, nM)
5-HT1A12–25 (Ki)
182–1,150 (EC50Tooltip half-maximal effective concentration)
5-HT1B0.08–0.36 (Ki)
0.10–1.8 (EC50)
94–100% (EmaxTooltip maximal efficacy)
5-HT1D0.06–0.48 (Ki)
0.27–0.83 (EC50)
97–99% (Emax)
5-HT1E1,150–1,700 (Ki)
>10,000 (EC50)
5-HT1F3,390–6,610 (Ki)
>10,000 (EC50)
5-HT2A182–447 (Ki)
7.9 (EC50)
5-HT2B813 (Ki)
25 (EC50)
5-HT2C575 (Ki) (rat)
ND (EC50)
5-HT3>10,000 (mouse)
5-HT42,000 (guinea pig)
5-HT5A813
5-HT62,340
5-HT7372–617 (Ki)
5,890 (EC50)
α1A–α1DND
α2A–α2CND
β1–β3ND
D1>10,000
D2>10,000
D3–D5ND
H1>10,000
H2>10,000
H3,H4ND
M1–M5ND
mACh>10,000
I1,I2>1,000
σ1,σ2ND
TAAR1Tooltip Trace amine-associated receptor 1ND
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 theserotonin5-HT1B (Ki = 0.079–0.40 nM;EmaxTooltip maximal efficacy = 94%) and5-HT1D receptors (Ki = 0.063–0.50 nM;Emax = 97%), and is among the mostpotent 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 serotonin5-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 atryptaminederivative, a 5-substituted derivative oftryptamine and5-methoxytryptamine, and ananalogue of thepsychedelic drugsdimethyltryptamine (DMT) and5-MeO-DMT.[12]

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

History

[edit]

Donitriptan was being developed inFrance bybioMérieux-Pierre Fabre and made it tophase IIclinical trials inEurope before development was discontinued.[14][15][16][3]

See also

[edit]

References

[edit]
  1. ^"Donitriptan".AdisInsight. 22 May 2000. Retrieved29 July 2025.
  2. ^Dukat M (March 2001). "Donitriptan (Pierre Fabre)".Current Opinion in Investigational Drugs.2 (3):415–418.PMID 11575714.
  3. ^abcdePerez, 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. Retrieved23 June 2025.
  4. ^abcJohn 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.doi:10.1016/S0022-3565(24)34871-2.PMID 10381763.
  5. ^abDe 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. ^abcRubio-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. Retrieved29 July 2025.
  8. ^van den Brink M (22 December 1999)."Coronary Side Effects of Antimigraine Drugs From Patient to Receptor".RePub, Erasmus University Repository. Retrieved19 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. Retrieved19 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. ^ab"Donitriptan".PubChem. Retrieved24 June 2025.
  13. ^"donitriptan".ChemSpider. 10 June 2024. Retrieved24 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.
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