ABSTRACT
In our pursuit to prepare a potent antipsychotic compound, a novel 1,2,3,4,6,6a,7,11b,12,12a-decahydropyrazino[2',1':6,1]pyrido[3,4-b]indole derivative was synthesized which incorporates the butyrophenone substructure twice. This molecule has shown D(1), D(2) and 5-HT(2A) receptor blocking activity where the ratio pK(i) (5-HT(2A)) to pK(i) (D(2)) is 1.42 better than risperidone (1.15). It blocks amphetamine induced hyperactivity/stereotypy and secondary conditioned avoidance responses in rodents at lower doses than those required for the neuroleptic drugs haloperidol and centbutindole (biriperone).
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Butanones , Dopamine D2 Receptor Antagonists , Drug Design , Indoles , Receptors, Dopamine D1/antagonists & inhibitors , Serotonin 5-HT2 Receptor Antagonists , Antipsychotic Agents/chemistry , Binding, Competitive , Butanones/chemical synthesis , Butanones/chemistry , Butanones/pharmacology , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are important for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT(2A) receptor binding affinities of these compounds suggests a possible role of 5-HT(2A) receptors in mediating the hypotensive action of title compounds.
