Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine

A CoMFA study was undertaken to elucidate the correlation of biological activity and structural parameters of 25 dopamine D4 antagonists. A special point of interest is that we have included the atypical D4 antagonist clozapine as a structural template for all other compounds. After comparing potential protonation sites at semiempirical (AM1) and ab initio (6-31G(d)) levels of theory, possible conformations of the lead compound 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo [1,5-a]pyridine (FAUC 113) were investigated by systematic semiempirical conformational analysis. The final conformation of FAUC 113, which was used as a template for the other compounds in the dataset, was chosen by clustering and rigid body alignment of all conformations to clozapine. The CoMFA applied on the final alignment resulted in a q(cv)(2) of 0.739. To elucidate the influence of the absolute orientation of the molecules within the grid space, the entire dataset was systematically rotated (1296 steps) within the lattice. The Gaussian-shaped distribution of the q(cv)(2) values spanned the range of 0.699-0.794 and therefore supports the significance of the analysis.