1-piperidines and Related Compounds, Potential Antipsychotic Agents with Low Cataleptogenic Profiles

Article abstract of DOI:10.1021/jm50001a013

On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-<3-(diarylamino)propyl>piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity.For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of <3H>haloperidol binding and in vivo in a test of locomotor activity.Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model.The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method.On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom.The 1-<3-(diarylamino)propyl>piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines.The compounds with the widest separation between efficacious dose and cataleptic dose are 8-<3-propyl>-1-phenyl-1,3,8-triazaspiro<4.5>decan-4-one (6), 1-<1-<3-propyl>-4-piperidinyl>-1,3-dihydro-2H-benzimidazol-2-one (11), 1-<1-<3-propyl>-1,2,3,6-tetrahydro-4-pyridinyl>-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-<3-propyl>-4-(2-methoxyphenyl)piperazine (26).