Antipsychotic drugs are psychiatric medication primarily used to manage psychosis (e.g., delusions or hallucinations), particularly in schizophrenia and bipolar disorder. First and second generations of antipshychotics tend to block receptors in the brain's dopamine pathways, but antipsychotic drugs encompass a wide range of receptor targets. The inhibition constant, K-i, at the level of membrane receptors is a major determinant of their pharmacokinetic behavior and, consequently, it can affect their antipsychotic activity. Here, predicted inhibition constants, K-i for 71 antipsychotics, already approved for clinical treatment, as well as representative new chemical structures which exhibit antipsychotic activity, were evaluated using 3D-QSAR-CoMSIA models. Significant values of the cross-validated correlation q(2) (higher than 0.70) and the fitted correlation r(2) (higher than 0.80) revealed that these models have reasonable power to predict the biological affinity of the 15 new risperidone and 12 new olanzapine derivatives in interactions with dopamine D-2 and serotonin 5HT(2A) receptors; these compounds are suggested for further studies.