A variety of data, from both animal and human behavioral investigations and receptor studies, implicates the sigma receptor in the actions of certain psychotomimetic drugs (benzomorphan opiates, PCP) and also certain novel antipsychotic drugs under development (rimcazole, remoxipride). Di-o-tolyl-guanidine (DTG), developed by consultants to CNS Research, appears to be one of the most selective and potent ligands for the sigma receptor and shows activity like that of the sigma receptor-binding antipsychotic drugs in bioassays. In order to characterize a series of DTG analogs for their drug development potential, CNS Research plans in Phase I of this project to: 1) examine the specificity of these compounds for the sigma receptor by a) additional receptor binding studies and b) synthesizing and testing radiolabeled versions of a few very high affinity analogs; 2) test the antagonist/agonist activity of the analogs in bioassays; and 3) determine the ability of the radiolabeled analogs to cross the blood- brain barrier. Based on these results, a lead compound(s) will be selected for further pharmaceutical development. In Phase II of this project, the extensive metabolic and toxicological testing required for an IND application will be performed on the best compound, and clinical trials arranged.
