Ritanserin, also known by its developmental code name R-55667, is a serotonin antagonist medication described as an

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

antiparkinsonian agent In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutr ...

, and

antihypertensive agent Antihypertensives are a class of medication, drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myo ...

. It was chiefly investigated as a drug to treat

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, 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 Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

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

scientific research The scientific method is an empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and medieval world. The ...

. 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 Oncology is a branch of medicine that deals with the study, treatment, diagnosis, and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's Etymology, etymological origin is the Greek word ὄγ ...

. Specifically, ritanserin acts as a potent inhibitor of diacylglycerol kinase alpha (DGKα). As such, it may be used to treat certain types of

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...

and

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

. 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 RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is genetic code, encoded by the ''RAF1'' gene. The c-Raf protein is part of the MAPK/ERK pathway, E ...

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 An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. It has relatively low

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

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 The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

risperidone Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is t ...

was developed from 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 Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

, and

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

. It was also found to improve

sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...

in human volunteers.

Synthesis

Aminothiazole (2-thiazolamine) (1) is condensed with 2-acetylbutyrolactone 17-23-7(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- ,3hiazolo

,2-a The comma is a punctuation mark that appears in several variants in different languages. Some typefaces render it as a small line, slightly curved or straight, but inclined from the vertical; others give it the appearance of a miniature fille ...

yrimidin-5-one
CID:82612453
(4). Halogenation of the terminal alcohol with phosphorus oxychloride then yields 6-(2-chloroethyl)- 7-methyl-5H-thiazolo

yrimidin-5-one, 6488-00-8(5). Alkylation with 4-(bis(4-fluorophenyl)methylene)piperidine, 8113-36-3(6) would complete the synthesis of ritanserin (7).

References

{{Serotonin receptor modulators 5-HT2A antagonists 5-HT2C antagonists Abandoned drugs CYP2D6 inhibitors Lactams 4-Fluorophenyl compounds Piperidines Thiazolopyrimidines