Benperidol is a typical first-generation neuroleptic with the chemical name 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2- a]pyrimidin-4-one. It is a piperazine phenylisoxazole derivative.
Benperidol consists of a central piperazine ring attached at one side to a phenylisoxazole unit and at the other side to a tetrahydropyridopyrimidine. The phenylene ring of the phenylisoxazole is substituted with fluorine at the 6-position. This chemical structure, particularly the phenylisoxazole unit and tetrahydropyridopyrimidine, gives benperidol its dopaminergic properties.
Benperidol binds with high affinity to dopamine D2 receptors in the dopaminergic pathways of the mesolimbic system, mesocortical system and nigrostriatal system. This leads to blockade of postsynaptic dopamine receptors, which in turn reduces dopaminergic neurochemical transmission. This is the primary mechanism by which benperidol exerts its antipsychotic effect.
Although benperidol binds highly to dopamine receptors, it also has moderate affinity for other receptors such as 5-HT2A, muscarinic M1, histamine H1 and noradrenaline α1 receptors. These additional pharmacological properties are responsible for many of the side effects of benperidol such as sedation, muscle twitching and dry mouth.
The complex chemical structure combined with the broad spectrum of activity contributes to the potential benefits of benperidol in treating psychoses such as schizophrenia, but is also causative of its significant side effects. Despite its historical importance, the clinical use of benperidol has been largely replaced today by newer atypical antipsychotics with a more favorable side effect profile.