AbstractSchizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D2, 5-HT1A, and 5-HT2Areceptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds1–16were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds1and10, selected based on their receptor profile, were subjected toin vivotests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D2, 5-HT1A, and 5-HT2Areceptors on the molecular level. Finally, X-ray study was conducted for compound1, which revealed its stable conformation in the solid state.