Structure analyses of R48455 a potent D 2 antagonist and its inactive isomer R49399

Abstract

In an attempt to identify the pharmacophore of D 2-antagonists, the crystal structure of the potent D 2-antagonist R48455 and its inactive geometrical isomer R49399 have been determined. Using PCILO calculations, it is shown that R48455 may adopt three low energy conformations with respect to rotation around the bond linking the cyclohexyl and the piperidine rings, whereas the inactive R49399 is rigidly locked in a single conformation corresponding to its crystal structure conformation. Employing the IFMFIT (interactive flexible molecular fitting) procedure, combined with X-ray data and PCILO results of tropapride and the title compounds, it is shown that the X-ray conformation of R48455 is most probably the biologically relevant one. Using the latter conformation as a template, a proposal is made as to the biologically relevant conformation of pimozide and spiperone.