Butyrophenone neuroleptic agents

In examining a large number of phenothaizines, butyrophenones and other neuroleptic agents both we and Seeman have demonstrated that there is an excellent correlation between the molar pharmacological potencies of these agents in animals and man and their affinities for H-haloperidol... 

Further studies into modifications of the butyrophe-nones in which the fiuoroketone functionality was replaced by a difiuorophenyl moiety resulted in the discovery of a group of neuroleptic agents, the diphenylbutylpiperidines. These compounds have similar levels of activity to the butyrophenones but have a longer duration of activity. 

The role of fluonne in the development of CNS agents has been reviewed [14] Ruonnated phenothiazines, typified by fluphenazine (7[Pg.1121]

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

Antipsychotic drugs include the older phenothiazines and butyrophenones, as well as newer atypical drugs. All of these can cause CNS depression, seizures, and hypotension. Some can cause QT prolongation. The potent dopamine D2 blockers are also associated with parkinsonian-like movement disorders (dystonic reactions) and in rare cases with the neuroleptic malignant syndrome, characterized by "lead-pipe" rigidity, hyperthermia, and autonomic instability (see Chapter 29 Antipsychotic Agents Lithium). 

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