7-[(4-Substituted phenyl-piperazin-1-yl)-alkoxyl]-4-methylchromene-2-ones as potential atypical antipsychotics: Synthesis and pharmacological evaluation

Abstract

7-Hydroxy-4-methylchromene-2-one <b style="">1</b> when reacted respectively with 2-bromo-1-chloroethane and 3-bromo-1-chloropropane in acetonitrile and in the presence of anhydrous K₂CO₃ yields 7-alkoxy-4-methylchromene-2-ones <b style="">2a,b</b>. Compounds <b style="">2a,b</b> when refluxed with various arylpiperazines in toluene and in the presence of triethylamine yield the title compounds, 7-[(4-substituted phenyl-piperazin-1-yl)-alkoxyl]-4-methylchromen-2-ones <b style="">3a-j</b>.Their atypical antipsychotic activity have been evaluated by their ability to inhibit apomorphine induced climbing behavior (D₂ antagonism) and to inhibit the 5–HTP induced head twitches in albino mice (5-HT_2A antagonism) alongwith catalepsy studies. All the compounds inhibit apomorphine induced climbing behavior and 5-HTP induced head twitches. The SAR studies reveal that methyl group in the phenyl ring of piperazine and the chain length (n=3) gives more dopaminergic and serotonergic antagonistic activity, while dichlorophenyl piperazines have less dopaminergic and serotonergic antagonistic activity. <b style="">3f</b> and <b style="">3g</b> have been found to have significant atypical behaviour.