This project delineates biochemical, chemical, and pharmacological properties of sigma receptors and ligands. Conformational analysis of the structures of sigma ligands have revealed a common pharmacophore, consisting of three hypothetical points. New selective sigma drugs, such as PRE-084, remoxipride and BMY-14802, were found to possess such a pharmacophore. Calculation of the electrostatic potential (ESP) on sigma ligands has generated the following common pattern: highest ESP is distributed in the center of the molecules, and the lowest ESP is around the periphery. These results may help design more selective sigma ligands for therapeutic usage. The discovery of sigma receptor subtypes in this laboratory, taken together with a comparison and examination of many actions of a ligands, have suggested that sigma-1 and sigma-2 receptors may have separate functions. A new, selective sigma ligand discovered in this laboratory, PRE-084, is under investigation. Using homogenate binding assays, sigma-1 and sigma-2 receptors were found to be distributed differentially among dissected regions of rat brain. Conditions for the selective labeling of the two types of a receptors in rat brain slices are now being established in order to allow precise visualization of anatomical location of these receptors via receptor autoradiography. Sigma receptors have been solubilized from membranes, and the solubilized receptors have been separated into two components with charge partition chromatography. Further purification of the receptors is underway.