Ritanserin

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Ritanserin
Ritanserin2DCSD.svg
Clinical data
Other namesR-55667; R55667; Tiserton
ATC code
  • None
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 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]

Contents

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 Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [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: 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).

See also

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References

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  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
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  17. ↑ 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.
  18. ↑ Prous J, Castaner J (May 1986). "Ritanserin". Drugs of the Future. 11 (5): 391. doi:10.1358/dof.1986.011.05.50826.
  19. ↑ US 4485107,Kennis LE, Vandenberk J, Mertens JC,issued 1984, assigned to Janssen Pharmaceutica N.V.
  20. ↑ EP 0110435,Kennis LE, Vandenberk J, Mertens JC,issued 1989, assigned to Janssen Pharmaceutica N.V.
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