Examination of a series of 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-aryl-1,3,8- triazaspiro[4.5]decan-4-ones as potential antipsychotic agents.
8-[3-[Bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8- triazaspiro[4.5]decan-4-one (3) and related compounds have been shown to have antipsychotic profiles in biochemical and behavioral pharmacological test models. The dose of 3 necessary to produce catalepsy in rats is much greater than that required for activity in behavioral tests predictive of antipsychotic efficacy, for example the suppression of high base line medial forebrain bundle self-stimulation in rats. This suggests that 3 would have a reduced propensity for neurological side effects. The effects of substitution on the 1-phenyl moiety and on the N-3 nitrogen atom of the triazaspirodecanone portion of 3 were examined. Results from this study suggest that behavioral activity is sensitive to substituents on the 1-phenyl moiety while substituents on the N-3 nitrogen are more generally tolerated. In both rats and squirrel monkeys compound 3 was found to have a similar separation between doses inhibiting Sidman avoidance activity and those causing catalepsy. However, in an extrapyramidal side effect (EPS) test model using haloperidol-sensitized cebus monkeys, 3 elicited signs of EPS at doses approximating those previously determined to be efficacious.
Wise
L D
LD
Pattison
I C
IC
Butler
D E
DE
DeWald
H A
HA
Lewis
E P
EP
Lobbestael
S J
SJ
Tecle
H
H
Coughenour
L L
LL
Downs
D A
DA
Poschel
B P
BP
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002428:Cebus; D055598:Chemical Phenomena; D002621:Chemistry; D006220:Haloperidol / Q000378:metabolism; D007031:Hypothalamus / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D012453:Saimiri; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D013141:Spiro Compounds; D006220:Haloperidol