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 pyrrolobenzazepinederivatives) 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.