Approximately ten percent of the world’s people suffer from psychosis. These people may be affected by schizophrenia or a schizophrenic-like disorder, a delirious condition, brief psychotic disorders, mania, an affective disorder with psychotic symptomatology, or a psychotic disorder from somatic disease. Antipsychotics, or neuroleptics, are needed to allow these people live normal lives.

These drugs do not completely cure people of psychosis, but they are very effective in treating the terrible symptoms. They sedate, calm, and improve the behavior of patients, allowing them to behave normally. Typical antipsychotics, the older medications, have many side effects. In order to reduce some of the side effects, atypical antipsychotics were developed in the 1990’s. The most recent type of antipsychotics, partial dopamine agonists, is now in the process of being developed.

Chemically, neuroleptics can be divided into six groups: phenothiazines, thioxanthenes, butyrophenones, dihydroindolones, dibenzoxazepines and dibenzdiazepines, diphenylbutylpiperidines, and others like sulpiride and lithium drugs. These drugs have varying structures and work in different ways.

Phenothiazines are mainly composed of a tricyclic system, the central ring of which contains a nitrogen atom and a sulfur atom. This is a picture of the molecular structure of Fluphenazine, a phenothiazine derivative:

The core structure of thioxanthene derivatives is the same as that of phenothiazines except the nitrogen atom is replaced by a carbon atom that is attached to a side chain. Thioxanthenes work the same way as phenothiazines and produce the same effects. Both types of drugs work by binding to the dopamine receptors, D1 and D2. This is a picture of how one thioxanthene derivative, chlorprothixene, is synthesized:

All butyrophenone derivatives are of the piperidine and piperazine series and have a pfluorobutyrophenone group. They act much like phenothiazines and thioxanthenes but mostly just bind to D2 receptors. The synthesis of a particular butyrophenone derivative, trifluperidol, is depicted here:

Diphenylbutylpiperidine derivatives are strong and long lasting. Their mechanism of action is mostly unknown, but they do slow dopaminergic activity. Penfluridol is synthesized through a Grignard reaction, alkaline hydrolysis, and alkylation:

Almost all antipsychotics work by blocking dopamine receptors (D1, D2, or D3 receptors) in the mesolimbic system of the brain. Phenothiazines block both D1 and D2 receptors whereas butyrophenones only bind to D2 receptors. Clozapine, a dibenzodiazepine derivative, is a poor blocker of dopamine receptors. It does reduce dopaminergic activity without blockage and antagonize 5-HT2A and 5-HT2C, to lessen negative symptoms.

The chemical groups of antipsychotics are all quite different structurally and have different mechanisms of action. Most of the drugs slow dopaminergic activity and they all sedate, calm, and reduce the psychosis of patients. They perform a great service to many people suffering from schizofrenia and other disorders.

By Mariel Hohmann

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