HIGH AFFINITY LIGANDS FOR SPECIFIC DOPAMINE RECEPTORS

THE DEVELOPMENT OF SAFER AND MORE EFFECTIVE ANTIPSYCHOTIC DRUGS REQUIRES THE AVAILABILITY OF SENSITIVE PROBES OF THE DOPAMINE (DA) RECEPTOR, WHICH IS A SITE OF ACTION OF THESE AGENTS. RESEARCH BIOCHEMICALS PROPOSES A PROGRAM TO PREPARE NOVEL SUBSTANCES WITH SELECTIVE AGONIST OR ANTAGONIST ACTION AT SPECIFIC DA RECEPTORS FOR USE BY RESEARCHERS IN NEUROPHARMACOLOGY. THE OBJECTIVES OF PHASE I RESEARCH ARE: 1. THE SYNTHESIS OF NOVEL APORPHINES AND RELATED COMPOUNDS WITH IRREVERSIBLE BINDING ACTIVITY AT DA RECEPTOR SITES. STRUCTURES WILL BE FORMULATED WITH PARTICULAR EMPHASIS ON SELECTIVE ACTIVITY AT PRESYNAPTIC DA AUTORECEPTORS. IRREVERSIBLE BINDING WILL BE ACCOMPLISHED WITH ALKYLATING AND/OR PHOTOACTIVATED FUNCTIONAL GROUPS. 2.THE INCORPORATION OF HIGHLY SELECTIVE DA RECEPTOR LIGANDS INTO A PRACTICAL AFFINITY COLUMN. THE PROTOTYPE OF THIS PRODUCT WILL BE A CLEBOPRIDE-FUNCTIONALIZED SUPPORT FOR USE IN ISOLATING DA D2 RECEPTORS. 3.THE PREPARATION OF HITHERTO UNAVAILABLE ENANTIOMERICALLY PURE PAIRS OF KNOWN DA AGONISTS AND ANTAGONISTS TO PERMIT STEREOCHEMICAL EXPLORATION OF RECEPTOR SURFACES. THE NEW PRODUCTS GENERATED IN PHASE I STUDIES WILL BE EVALUATED FOR COMMERICAL INTRODUCTION TO THE EXPANDING NEUROSCIENTIFIC COMMUNITY.