Chemistry:Ritanserin

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Short description: Chemical compound
Ritanserin
Ritanserin2DCSD.svg
Clinical data
Other namesR-55667; R55667; Tiserton
ATC code
  • None
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC27H25F2N3OS
Molar mass477.57 g·mol−1
3D model (JSmol)
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Ritanserin, also known by its developmental code name R-55667, is a serotonin antagonist medication described as an anxiolytic, antidepressant, antiparkinsonian agent, and antihypertensive agent.[1][2][3] It was chiefly investigated as a drug to treat insomnia, especially to enhance sleep quality by significantly increasing slow wave sleep by virtue of potent and concomitant 5HT2a and 5HT2c antagonism[4][5]

It was never marketed for medical use due to safety problems but is currently used in scientific research.

Some of the safety liabilities that lead to its discontinuation for the treatment of insomnia has led to its potential repurposing in the field of oncology. Specifically, ritanserin acts as a potent inhibitor of diacylglycerol kinase alpha (DGKα). As such, it may be used to treat certain types of glioblastoma[6][7] 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.[8]

Additionally, ritanserin blocks c-RAF activation and induces apoptotic cell death of non–small cell lung cancer and small cell lung cancer cells.[9]

Pharmacology

Pharmacodynamics

Ritanserin acts as a selective 5-HT2A (Ki = 0.45 nM) and 5-HT2C receptor (Ki = 0.71 nM) antagonist.[10][11] 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).[11] The affinity of ritanserin for the 5-HT1A receptor is less than 1 μM.[11] 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.[12]

History

The atypical antipsychotic risperidone was developed from ritanserin.[13]

Society and culture

Names

Ritanserin is the generic name of the drug and its INN, USAN, and BAN.[2][1] It is also known by its developmental code name R-55667.[1]

Availability

Ritanserin was never approved or marketed for medical use.[14][15][16]

Research

Ritanserin was tested in clinical trials for depression,[3] anxiety, schizophrenia,[10] and migraine.[17] It was also found to improve sleep in human volunteers.[16]

Synthesis

Synthesis:[18] Patents:[19][20]

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).

See also

References

  1. ↑ 1.0 1.1 1.2 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. p. 411. ISBN 978-1-4757-2085-3. OCLC 1058412474. https://books.google.com/books?id=0vXTBwAAQBAJ. 
  2. ↑ 2.0 2.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 249–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA249. 
  3. ↑ 3.0 3.1 Handbook of Chronic Depression: Diagnosis and Therapeutic Management. CRC Press. 14 May 2014. pp. 117–. ISBN 978-0-8247-5660-4. https://books.google.com/books?id=KFVPlzuOX88C&pg=PA117. 
  4. ↑ "Effects of ritanserin on sleep disturbances of dysthymic patients". Psychopharmacology 96 (3): 395–9. 1988. doi:10.1007/BF00216069. PMID 3146774. 
  5. ↑ "5-Hydroxytryptamine-2 antagonist increases human slow wave sleep". Brain Research 378 (1): 164–8. July 1986. doi:10.1016/0006-8993(86)90299-4. PMID 3091188. 
  6. ↑ "Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha". Neuro-Oncology 20 (2): 192–202. January 2018. doi:10.1093/neuonc/nox119. PMID 29048560. 
  7. ↑ "Ritanserin, a novel agent targeting the mesenchymal subtype of glioblastomas". Neuro-Oncology 20 (2): 151–152. January 2018. doi:10.1093/neuonc/nox240. PMID 29365204. 
  8. ↑ "Identification of ritanserin analogs that display DGK isoform specificity". Biochemical Pharmacology 197: 114908. March 2022. doi:10.1016/j.bcp.2022.114908. PMID 34999054. 
  9. ↑ "Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells". Molecular Pharmacology 94 (5): 1246–1255. November 2018. doi:10.1124/mol.118.113001. PMID 30158316. 
  10. ↑ 10.0 10.1 "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. December 2008. doi:10.1016/j.pnpbp.2008.08.020. PMID 18801405. 
  11. ↑ 11.0 11.1 11.2 "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. June 1985. PMID 2860558. https://pubmed.ncbi.nlm.nih.gov/2860558. 
  12. ↑ Harmful Non-Indigenous Species in the United States. DIANE Publishing. 1 February 1993. pp. 361–. ISBN 978-0-7881-0441-1. https://books.google.com/books?id=wSnzKXFtuKwC&pg=PA361. 
  13. ↑ "Atypical Antipyschotics based on the D2/5-HT2 ratio hypothesis". Current Medicinal Chemistry. Bentham Science Publishers. May 1994. pp. 52–. https://books.google.com/books?id=JMd5FWm6GTkC&pg=PA52. 
  14. ↑ "Micromedex Products: Please Login". https://www.micromedexsolutions.com/micromedex2/librarian/. 
  15. ↑ Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society. ed. Index Nominum 2000: International Drug Directory. Taylor & Francis. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC. 
  16. ↑ 16.0 16.1 "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacological Reviews 70 (2): 197–245. April 2018. doi:10.1124/pr.117.014381. PMID 29487083. 
  17. ↑ "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. June 1990. doi:10.1111/j.1526-4610.1990.hed3007439.x. PMID 2119355. 
  18. ↑ "Ritanserin". Drugs of the Future 11 (5): 391. May 1986. doi:10.1358/dof.1986.011.05.50826. 
  19. ↑ Kennis LE, Vandenberk J, Mertens JC, US patent 4485107, issued 1984, assigned to Janssen Pharmaceutica N.V.
  20. ↑ Kennis LE, Vandenberk J, Mertens JC, EP patent 0110435, issued 1989, assigned to Janssen Pharmaceutica N.V.



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