1-[3-(Diarylamino)propyl]piperidines and related compounds, potential antipsychotic agents with low cataleptogenic profiles.
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).
Wise
L D
LD
Pattison
I C
IC
Butler
D E
DE
DeWald
H A
HA
Lewis
E P
EP
Lobbestael
S J
SJ
Nordin
I C
IC
Poschel
B P
BP
Coughenour
L L
LL
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000633:toxicity; D001480:Basal Ganglia Diseases / Q000139:chemically induced; D001667:Binding, Competitive; D002375:Catalepsy / Q000139:chemically induced*; D003342:Corpus Striatum / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012653:Self Stimulation / Q000187:drug effects; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D010879:Piperazines; D010880:Piperidines; D011954:Receptors, Dopamine; D006220:Haloperidol