The chemical development of selective and specific serotonin S₂‐antagonists

Four types of chemical intermediates were prepared to synthesize novel piperidine derivatives inspired by the butyrophenones benperidol and lenperone and by the diphenylbutyl neuroleptic pimozide. The fist type, comprising benzimidazolone alkyl intermediates, yielded declenperone and milenperone and also the “symmetrical” compound domperidone, which was pharmacologically unusual by its specific peripheral dopamine antagonism. Declenperone was the most potent serotonin antagonist of that series, and replacement of the benzimidazolinonepropyl by the quinazolinedioneethyl moiety led to ketanserin, which was devoid of residual dopamine antagonism. Very potent serotonin S 2 ‐antagonists were also obtained by using intermediates prepared from 2‐aminoaza‐heterocycles. Pirenperone and setoperone had a complex pharmacological profile, including significant dopamine and norepinephrine antagonism. These activity components were absent from the profile of R 56413 and ritanserin, which were obtained by using the fourth intermediate, benzhydrylenepiperidine. R 56413 and ritanserin are the most specific of the presently known serotonin S 2 ‐antagonists.