DITOLYL GUANIDINE ANALOGS AS ANTIPSYCHOTIC DRUGS

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-TOLYLGUANIDINE (DTG) 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. TO CHARACTERIZE A SERIES OF DTG ANALOGS FOR THEIR DRUG DEVELOPMENT POTENTIAL, PHASE I EFFORTS WILL: (1) EXAMINE THESPECIFICITY OF THESE COMPOUNDS FOR THE SIGMA RECEPTOR BY ADDITIONAL RECEPTOR-BINDING STUDIES AND BY 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, LEAD COMPOUNDS WILL BE SELECTED FOR FURTHER PHARMACEUTICAL DEVELOPMENT. IN PHASE II, THE EXTENSIVE METABOLIC AND TOXICOLOGICAL TESTING REQUIRED FOR AN INVESTIGATIONAL NEW DRUG APPLICATION WILL BE PERFORMED ONTHE BEST COMPOUND, AND CLINICAL TRIALS ARRANGED.