Ritanserin

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. 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-HT_2A and 5-HT_2C receptor antagonism. The drug is taken orally.

Pharmacology

Pharmacodynamics

Ritanserin acts as a selective 5-HT_2A and 5-HT_2C receptor antagonist. It has relatively low affinity for the H₁, D₂, α₁-adrenergic, and α₂-adrenergic receptors. 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.
Ritanserin blocks c-RAF activation and induces apoptotic cell death of non–small cell lung cancer and small cell lung cancer cells.

Pharmacokinetics

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

Chemistry

Synthesis

is condensed with 2-acetylbutyrolactone 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--7-methyl-thiazolopyrimidin-5-one, . Halogenation of the terminal alcohol with phosphorus oxychloride then yields 6-- 7-methyl-5H-thiazolopyrimidin-5-one, . Alkylation with 4-piperidine, would complete the synthesis of ritanserin.

History

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

Society and culture

Names

Ritanserin is the generic name of the drug and its,, and. 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. It reached phase 3 clinical trials for major depressive disorder prior to the discontinuation of its development.
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. 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.