ABSTRACT
The discovery, synthesis and structure-activity studies of a novel series of 2-arylpyrimidin-4-ones as CRF-1 receptor antagonists is described. These compounds are structurally simple and display appropriate physical properties for CNS agents
Subject(s)
Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Chemical Phenomena , Chemistry, Physical , Drug Design , Humans , In Vitro Techniques , Indicators and Reagents , Microsomes/drug effects , Structure-Activity RelationshipABSTRACT
5-piperazinyl-1,2,6,7-tetrahydro-5H-azepino[3,2,1-hi]indol-4-one derivatives were designed, synthesized, and identified as a new series of mixed dopamine D(2)/D(4) receptor antagonists. This series featured a rigid tricyclic ring system as an important pharmacophore core structure for high binding affinity. Molecular modeling studies are also described.
Subject(s)
Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Indoles/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Molecular , Monte Carlo Method , Protein Binding , Radioligand Assay , Receptors, Dopamine D4 , Structure-Activity RelationshipABSTRACT
Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported.
Subject(s)
Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Indoles/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Binding, Competitive/drug effects , Glycine/chemistry , Humans , In Vitro Techniques , Prazosin/metabolism , Rats , Receptors, Dopamine D4 , Recombinant Proteins/drug effects , Structure-Activity RelationshipABSTRACT
A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.
