Molecular field analysis of clozapine analogs in the development of a pharmacophore model of antipsychotic drug action.

In an attempt to elucidate some aspects of clozapine's favorable receptor binding profile, we modeled a series of 30 clozapine analogs using a pharmacophore based on the ligands octoclothepin and tefludazine. Molecular field analysis using CoMFA combined with HINT was carried out on published D2 receptor binding affinities. Several alternative alignments of the analogs gave r2 values in the range of 0.8-0.95. The final model had good predictive abilities with q2 > 0.6 and r2 > 0.9. This provides an excellent framework to aid in the design of novel antipsychotics with diminished propensity to produce clinically limiting side effects.