In this study, a series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities of the target compounds were evaluated in vitro and in vivo. The results showed that synthesized compounds 7a-7g decreased the activity of dopamine D-2 receptors in HEK293 cells co-transfected with D-2 receptor/G protein alpha 16a, with IC50 values of 0.051-0.35 mu m. Compounds 7a-7g inhibited the over-production of nitric oxide stimulated by lipopolysaccharide/interferon-gamma in BV-2 microglial cells. In mice, intragastric administration of 7d, 7e, and 7g reversed the increase in locomotor activity induced by MK-801 (an antagonist of NMDA receptors) and decreased the hyperactivity of climbing behavior induced by apomorphine (a dopamine receptor agonist). These results suggest that some of the novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia.