Document Detail

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.
MedLine Citation:
PMID:  2866248     Owner:  NLM     Status:  MEDLINE    
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.
L D Wise; I C Pattison; D E Butler; H A DeWald; E P Lewis; S J Lobbestael; H Tecle; L L Coughenour; D A Downs; B P Poschel
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  28     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1985 Dec 
Date Detail:
Created Date:  1986-01-16     Completed Date:  1986-01-16     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1811-7     Citation Subset:  IM    
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MeSH Terms
Antipsychotic Agents / chemical synthesis,  pharmacology*
Avoidance Learning / drug effects
Behavior, Animal / drug effects
Catalepsy / chemically induced
Chemical Phenomena
Haloperidol / metabolism
Hypothalamus / physiology
Motor Activity / drug effects
Receptors, Adrenergic, alpha / metabolism
Receptors, Dopamine / drug effects,  metabolism
Receptors, Muscarinic / metabolism
Spiro Compounds / chemical synthesis,  metabolism,  pharmacology*
Structure-Activity Relationship
Reg. No./Substance:
0/Antipsychotic Agents; 0/Receptors, Adrenergic, alpha; 0/Receptors, Dopamine; 0/Receptors, Muscarinic; 0/Spiro Compounds; 52-86-8/Haloperidol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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