Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT(1A), and adrenergic α1 receptors

Article abstract of DOI:10.1021/jm970164z

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D₂, serotonin 5- HT(1A), and α₁-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1- methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.