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. 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 5-HT_2A and 5-HT_2C receptor antagonism.

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

Some of the safety liabilities that led 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 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.

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

Pharmacology

Pharmacodynamics

Ritanserin acts as a selective 5-HT_2A (K_i = 0.45 nM) and 5-HT_2C receptor (K_i = 0.71 nM) antagonist. 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-HT_2A, respectively). The affinity of ritanserin for the 5-HT_1A receptor is less than 1 μM. In addition to its affinity for the 5-HT_2A and 5-HT_2C receptors, ritanserin also binds to and antagonizes the 5-HT_1D, 5-HT_2B, 5-HT_5A, 5-HT₆, and 5-HT₇ receptors.

History

The atypical antipsychotic risperidone was developed from ritanserin.

Society and culture

Names

Ritanserin is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name. It is also known by its developmental code name R-55667.

Availability

Ritanserin was never approved or marketed for medical use.

Research

Ritanserin was tested in clinical trials for depression, anxiety, schizophrenia, and migraine. It was also found to improve sleep in human volunteers.

Synthesis

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).