1-[3-(Diarylamino)propyl]piperidines and Related Compounds, Potential Antipsychotic Agents with Low Cataleptogenic Profiles

• Published in: Journal of medicinal chemistry Vol. 28; no. 5; pp. 606 - 612
• Main Authors: Wise, Lawrence D, Pattison, Ian C, Butler, Donald E, DeWald, Horace A, Lewis, Edward P, Lobbestael, Sandra J, Nordin, Ivan C, Poschel, B. P. H, Coughenour, Linda L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.05.1985
• Subjects: Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - toxicity; Basal Ganglia Diseases - chemically induced; Binding, Competitive; Catalepsy - chemically induced; Chemistry; Corpus Striatum - metabolism; Exact sciences and technology; Haloperidol - metabolism; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; In Vitro Techniques; Male; Mice; Motor Activity - drug effects; Organic chemistry; Piperazines - chemical synthesis; Piperazines - pharmacology; Piperazines - toxicity; Piperidines - chemical synthesis; Piperidines - pharmacology; Piperidines - toxicity; Preparations and properties; Rats; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Self Stimulation - drug effects; Structure-Activity Relationship; Five membered ring; Nitrogen heterocycle; Six membered ring; Lactam; Bicyclic compound; Antipsychotic; Ureas; Aromatic compound; Biological activity; Spiran
• DOI: 10.1021/jm50001a013
• ISSN: 0022-2623

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-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).