NOVEL, NEMATODE-SPECIFIC ANTHELMINTICS AND NEMATICIDES

OUR PURPOSE IS TO DEVELOP NEW NEMATICIDES AND ANTHELMINTICS WHICH ARE NEMATODE-SPECIFIC AND WHICH HAVE A NOVEL MODE OF ACTION. OUR APPROACH INVOLVES DETAILED STUDIES OF THE NEMATODE RECEPTORS FOR GLUTAMIC ACID (GLU) AND 5-HYDROXYTRYPTAMINE (SEROTONIN). PHASE I INCLUDES BEHAVIORAL AND ELECTROPHYSIOLOGICAL EXPERIMENTS TO IDENTIFY COMPOUNDS ACTIVE AT THE NEMATODE GLU AND SEROTONIN RECEPTORS, GENETIC EXPERIMENTS DESIGNED TO PRODUCE RAPID SCREENS FOR ADDITIONAL COMPOUNDS ACTIVE AT THESE RECEPTORS, AND THE DEVELOPMENT OF LIGAND-BINDING ASSAYS. DURING PHASE II WE WILL USE THE SCREENS TO IDENTIFY NOVEL LEAD COMPOUNDS WHICH ARE ACTIVE AT THE NEMATODE GLU AND SEROTONIN RECEPTORS. WE WILL USE THE LIGAND-BINDING ASSAY TO PERFORM STRUCTURE-ACTIVITY STUDIES ON ANALOGUES OF THESE LEAD COMPOUNDS IN ORDER TO DISCOVER CHEMICAL MODIFICATIONS WHICH INCREASE THEIR SPECIFICITY FOR THE NEMATODE RECEPTOR AS COMPARED TO THE HOMOLOGOUS MAMMALIAN RECEPTORS. MODIFICATION OF THE MOST NEMATODE-SPECIFIC COMPOUNDS TO EMERGE FROM THIS WORK GUIDED BY IN VIVO ASSAYS ON PARASITES (PHASE III), WILL YIELD NOVEL, NEMATODE-SPECIFIC ANTHELMINTICS AND NEMATICIDES.