Rational design, synthesis and evaluation of (6aR∗,11bS∗)-1-(4-fluorophenyl)-4-{7-[4-(4-fluorophenyl)-4-oxobutyl]1,2,3,4,6,6a,7,11b,12,12a(RS)-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indol-2-yl}-butan-1-one as a potential neuroleptic agent

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 D1, D2 and 5-HT2A receptor blocking activity where the ratio pKi (5-HT2A) to pKi (D2) 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).

Synthesis and potent neuroleptic activity of a novel 1,2,3,4,6,6a,7,11b,12,12a-decahydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole derivative having D1, D2, and 5-HT2A receptor blocking activity (pKi (5-HT2A)/pKi (D2) = 1.42) is reported.Figure optionsDownload as PowerPoint slide