Ritanserin

Last updated
Ritanserin
Ritanserin2DCSD.svg
Clinical data
Other namesR-55667; R55667; Tiserton
Routes of
administration 		Oral [1]
Drug class Serotonin 5-HT2 receptor antagonist; Serotonin 5-HT2A receptor antagonist
ATC code
  • None
Pharmacokinetic data
Onset of action 1.7 hours (Tmax Tooltip time to peak levels) [2]
Elimination half-life 54 hours [2]
Identifiers
  • 6-[2-[4-[bis(4-fluorophenyl)methylidene]piperidin-1-yl]ethyl]-7-methyl-[1,3]thiazolo[2,3-b]pyrimidin-5-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.163.772 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H25F2N3OS
Molar mass 477.57 g·mol−1
3D model (JSmol)
  • CC1=C(C(=O)N2C=CSC2=N1)CCN3CCC(=C(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F)CC3
  • InChI=1S/C27H25F2N3OS/c1-18-24(26(33)32-16-17-34-27(32)30-18)12-15-31-13-10-21(11-14-31)25(19-2-6-22(28)7-3-19)20-4-8-23(29)9-5-20/h2-9,16-17H,10-15H2,1H3 X mark.svgN
  • Key:JUQLTPCYUFPYKE-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ritanserin, also known by its developmental code name R-55667, is a serotonin receptor antagonist which was under development for the treatment of anxiety disorders and major depressive disorder but was never marketed. [1] [3] [4] [5] It was also investigated for treatment of insomnia, especially to enhance sleep quality by significantly increasing slow wave sleep by virtue of potent and concomitant serotonin 5-HT2A and 5-HT2C receptor antagonism. [6] [7] The drug is taken orally. [1]

Contents

Pharmacology

Pharmacodynamics

Ritanserin acts as a selective 5-HT2A (Ki = 0.45 nM) and 5-HT2C receptor (Ki = 0.71 nM) antagonist. [8] [9] It has relatively low affinity for the H1, D2, α1-adrenergic, and α2-adrenergic receptors (39-, 77-, 107-, and 166-fold lower relative to 5-HT2A, respectively). [9] The affinity of ritanserin for the 5-HT1A receptor is less than 1 μM. [9] In addition to its affinity for the 5-HT2A and 5-HT2C receptors, ritanserin also binds to and antagonizes the 5-HT1D, 5-HT2B, 5-HT5A, 5-HT6, and 5-HT7 receptors. [10]

Ritanserin blocks c-RAF activation and induces apoptotic cell death of non–small cell lung cancer and small cell lung cancer cells. [11]

Pharmacokinetics

The time to peak levels of ritanserin is 1.7 hours. [2] Its elimination half-life is 54 hours. [2]

Chemistry

Synthesis

Synthesis: Patents: Ritanserin synthesis.svg
Synthesis: Patents:

Aminothiazole (2-thiazolamine) (1) is condensed with 2-acetylbutyrolactone [517-23-7] (2) under DS-trap until the water has separated. Condensation of this β-keto lactone can be visualized to involve initial attack on the reactive butyrolactone by the primary nitrogen; cyclodehydration of that hypothetical intermediate 3 gives 6-(2-hydroxyethyl)-7-methyl-[1,3]thiazolo[3,2-a]pyrimidin-5-one, CID:82612453 (4). Halogenation of the terminal alcohol with phosphorus oxychloride then yields 6-(2-chloroethyl)- 7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, [86488-00-8] (5). Alkylation with 4-(bis(4-fluorophenyl)methylene)piperidine, [58113-36-3] (6) would complete the synthesis of ritanserin (7).

History

The atypical antipsychotic risperidone was developed via structural modification of ritanserin. [15]

Society and culture

Names

Ritanserin is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [4] [3] It is also known by its developmental code name R-55667. [3]

Availability

Ritanserin was never approved or marketed for medical use. [16] [17] [18]

Research

Ritanserin was tested in clinical trials for depression, [5] anxiety, schizophrenia, [8] and migraine. [19] It was also found to improve sleep in human volunteers. [18] It reached phase 3 clinical trials for major depressive disorder prior to the discontinuation of its development. [1]

Some of the safety liabilities that led to its discontinuation of ritanserin for treatment of insomnia have led to its potential repurposing in the field of oncology. Specifically, it acts as a potent inhibitor of diacylglycerol kinase alpha (DGKα). As such, it may be used to treat certain types of glioblastoma [20] [21] and melanoma. It has also been used as a reference compound to identify putatively more selective and potent DGKα inhibitors to treat these forms of cancer as well as possibly others. [22]

See also

References

  1. 1 2 3 4 "Ritanserin". AdisInsight. 7 January 1997. Retrieved 16 January 2026.
  2. 1 2 3 4 Barone JA, Bierman RH, Cornish JW, Hsuan A, Drake ND, Colaizzi JL (October 1986). "Safety evaluation of ritanserin--an investigational serotonin antagonist". Drug Intell Clin Pharm. 20 (10): 770–775. doi:10.1177/106002808602001006. PMID   3095082. Plasma level determinations were made two hours postdose because preliminary European studies in three normal male subjects indicated that peak plasma levels occurred at 1.7 ± 0.06 h (mean ± SO). 16 Therefore, the two-hour plasma level was within the vicinity of the Cmax • This preliminary study suggested a half-life of 54 ± II h for the tablet treatment with a 25 mg dose. Such a long half-life may explain why there were detectable levels following some placebo treatments and during some of the follow-up determinations.
  3. 1 2 3 Elks J, ed. (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 411. ISBN   978-1-4757-2085-3. OCLC   1058412474.
  4. 1 2 Morton I, Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 249–. ISBN   978-0-7514-0499-9.
  5. 1 2 Alpert JE, Fava M, Alpert JE, eds. (14 May 2014). Handbook of Chronic Depression: Diagnosis and Therapeutic Management. CRC Press. pp. 117–. ISBN   978-0-8247-5660-4.
  6. ↑ Paiva T, Arriaga F, Wauquier A, Lara E, Largo R, Leitao JN (1988). "Effects of ritanserin on sleep disturbances of dysthymic patients". Psychopharmacology. 96 (3): 395–9. doi:10.1007/BF00216069. PMID   3146774. S2CID   19232592.
  7. ↑ Idzikowski C, Mills FJ, Glennard R (July 1986). "5-Hydroxytryptamine-2 antagonist increases human slow wave sleep". Brain Research. 378 (1): 164–8. doi: 10.1016/0006-8993(86)90299-4 . PMID   3091188. S2CID   43604995.
  8. 1 2 Akhondzadeh S, Malek-Hosseini M, Ghoreishi A, Raznahan M, Rezazadeh SA (December 2008). "Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 32 (8): 1879–1883. doi:10.1016/j.pnpbp.2008.08.020. PMID   18801405. S2CID   12270281.
  9. 1 2 3 Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PF, Laduron PM (June 1985). "Receptor-binding properties in vitro and in vivo of ritanserin: A very potent and long acting serotonin-S2 antagonist". Molecular Pharmacology. 27 (6): 600–611. doi:10.1016/S0026-895X(25)12558-3. PMID   2860558.
  10. ↑ Harmful Non-Indigenous Species in the United States. DIANE Publishing. 1 February 1993. pp. 361–. ISBN   978-0-7881-0441-1.
  11. ↑ Campbell ST, Franks CE, Borne AL, Shin M, Zhang L, Hsu KL (November 2018). "Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells". Molecular Pharmacology. 94 (5): 1246–1255. doi:10.1124/mol.118.113001. PMC   6160665 . PMID   30158316.
  12. ↑ Prous J, Castaner J (May 1986). "Ritanserin". Drugs of the Future. 11 (5): 391. doi:10.1358/dof.1986.011.05.50826.
  13. ↑ US 4485107,Kennis LE, Vandenberk J, Mertens JC,issued 1984, assigned to Janssen Pharmaceutica N.V.
  14. ↑ EP 0110435,Kennis LE, Vandenberk J, Mertens JC,issued 1989, assigned to Janssen Pharmaceutica N.V.
  15. ↑ Lowe III JA (May 1994). "Atypical Antipyschotics based on the D2/5-HT2 ratio hypothesis". Current Medicinal Chemistry. Bentham Science Publishers. pp. 52–.
  16. ↑ "Micromedex Products: Please Login".
  17. ↑ Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. ISBN   978-3-88763-075-1.
  18. 1 2 Atkin T, Comai S, Gobbi G (April 2018). "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacological Reviews. 70 (2): 197–245. doi: 10.1124/pr.117.014381 . PMID   29487083. S2CID   3578916.
  19. ↑ Nappi G, Sandrini G, Granella F, Ruiz L, Cerutti G, Facchinetti F, et al. (June 1990). "A new 5-HT2 antagonist (ritanserin) in the treatment of chronic headache with depression. A double-blind study vs amitriptyline". Headache. 30 (7): 439–444. doi:10.1111/j.1526-4610.1990.hed3007439.x. hdl: 11380/740716 . PMID   2119355. S2CID   25781431.
  20. ↑ Olmez I, Love S, Xiao A, Manigat L, Randolph P, McKenna BD, et al. (January 2018). "Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha". Neuro-Oncology. 20 (2): 192–202. doi:10.1093/neuonc/nox119. PMC   5777487 . PMID   29048560.
  21. ↑ Audia A, Bhat KP (January 2018). "Ritanserin, a novel agent targeting the mesenchymal subtype of glioblastomas". Neuro-Oncology. 20 (2): 151–152. doi:10.1093/neuonc/nox240. PMC   5786216 . PMID   29365204.
  22. ↑ Granade ME, Manigat LC, Lemke MC, Purow BW, Harris TE (March 2022). "Identification of ritanserin analogs that display DGK isoform specificity". Biochemical Pharmacology. 197 114908. doi:10.1016/j.bcp.2022.114908. PMC   8858877 . PMID   34999054.
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