Quantitative structure – activity relationship studies on membrane receptors inhibition by antipsychotic drugs. Application to schizophrenia treatment

There are presented six new QSAR models, which are correlating antipsychotic activity ( pK i values at dopamine D1–D4 and serotonine (5-HT2C, 5-HT2A) receptors) with physicochemical parameters. A large data set of typical and atypical antipsychotics already approved for clinical treatment including as well representatives with new chemical structures which are exhibiting antipsychotic activity (tetrahydrofuran-, benzamide-, 3-aminoethyl-1-tetralones-, piperazine-, benzothiazepine- and pyrrolobenzazepine-derivatives) were incorporated within this study. The appropriate 2D and internal-3D molecular descriptors could be generated by use of the computational software MOE (Molecular Operating Environment). Significant q 2 (0.63–0.76) and r 2 (0.70–0.78) correlation coefficients were obtained, indicating that the established equations can be used within a wide range of binding constants ( pK i = 5 to 9.76). By use of these linear models an assembly of new aripiprazole structures could be established. Some of them are showing significantly improved antipsychotic activity in comparison with the parent compound.