Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and ,in vitro Scaffold jumping among five: and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact. on these effects. Potent and selective. dopamine D-2 receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran. was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC)levels correlated very Well With their affinity for dopamine D-2 receptors and MAO A In the 4-arylpiperidine series, the most promising compound. for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D2 receptor antagonist properties in vivo but produced only a partial. reduction on spontaneous locomotor activity; This indicates: that the compound may have a lower propensity to induce parkinsonism in patients