Ritanserin

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 never marketed for medical use due to safety problems but has been used in scientific research to study the serotonin system.[2][4]

Ritanserin
Clinical data
Other namesR-55667; R55667; Tiserton
ATC code
  • None
Identifiers
IUPAC name
  • 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 InfoCard100.163.772
Chemical and physical data
FormulaC27H25F2N3OS
Molar mass477.57 g·mol−1
3D model (JSmol)
SMILES
  • CC1=C(C(=O)N2C=CSC2=N1)CCN3CCC(=C(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F)CC3
InChI
  • 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 N
  • Key:JUQLTPCYUFPYKE-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

Pharmacology

Pharmacodynamics

Ritanserin acts as a selective 5-HT2A (Ki = 0.45 nM) and 5-HT2C receptor (Ki = 0.71 nM) antagonist.[5][6] 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).[6] The affinity of ritanserin for the 5-HT1A receptor is less than 1 μM.[6] 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.[7]

History

The atypical antipsychotic risperidone was developed from ritanserin.[8]

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.[9][10][4]

Research

Ritanserin was tested in clinical trials for depression,[3] anxiety, schizophrenia,[5] and migraine.[11] It was also found to improve sleep in human volunteers.[4]

Synthesis
Synthesis:[12] Patents:[13][14]

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. J. Elks, 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.
  2. Dr. Ian Morton; I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 249–. ISBN 978-0-7514-0499-9.
  3. Jonathan Edward Alpert (14 May 2014). Jonathan Edward Alpert; Maurizio Fava (eds.). Handbook of Chronic Depression: Diagnosis and Therapeutic Management. CRC Press. pp. 117–. ISBN 978-0-8247-5660-4.
  4. Atkin T, Comai S, Gobbi G (April 2018). "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacol Rev. 70 (2): 197–245. doi:10.1124/pr.117.014381. PMID 29487083. S2CID 3578916.
  5. Akhondzadeh S, Malek-Hosseini M, Ghoreishi A, Raznahan M, Rezazadeh SA (September 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): 1879–83. doi:10.1016/j.pnpbp.2008.08.020. PMID 18801405. S2CID 12270281.
  6. Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PF, Laduron PM (1985). "Receptor-binding properties in vitro and in vivo of ritanserin: A very potent and long acting serotonin-S2 antagonist". Mol Pharmacol. 27 (6): 600–11. PMID 2860558.
  7. Harmful Non-Indigenous Species in the United States. DIANE Publishing. 1 February 1993. pp. 361–. ISBN 978-0-7881-0441-1.
  8. Bentham Science Publishers (May 1994). Current Medicinal Chemistry. Bentham Science Publishers. pp. 52–.
  9. "Micromedex Products: Please Login".
  10. Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. ISBN 978-3-88763-075-1.
  11. Nappi, G; Sandrini, G; Granella, F; Ruiz, L; Cerutti, G; Facchinetti, F; Blandini, F; Manzoni, GC (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): 439–44. doi:10.1111/j.1526-4610.1990.hed3007439.x. hdl:11380/740716. PMID 2119355. S2CID 25781431.
  12. Prous, J.; Castaner, J.; Ritanserin. Drugs Fut 1986, 11, 5, 391.
  13. Ludo E. J. Kennis, Jan Vandenberk, Josephus C. Mertens, U.S. Patent 4,485,107 (1984 to Janssen Pharmaceutica N.V.)
  14. Ludo Edmond Josephine Kennis, et al. EP 0110435 (1989 to Janssen Pharmaceutica NV).


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