SELECTIVE DOPAMINE D-1 AND D-2 FLUORESCENT PROBES

DYSFUNCTION OF DOPAMINE SYSTEMS IN THE BRAIN HAVE BEEN IMPLICATED IN ENDOCRINE, NEUROLOGICAL AND PSYCHIATRIC DISORDERS, AND DOPAMINERGIC DRUGS ARE WIDELY PRESCRIBED FOR THESE DISORDERS. BRAIN DOPAMINE RECEPTORS ARE CLEARLY IMPLICATED AS THE TARGETS OF THESE DRUGS. THESE RECEPTORS ARE IN A MOBILE, DYNAMIC STATE AND CAN BE MODULATED BY DRUGS, LESIONS, DISEASES, HORMONES AND OTHER CHALLENGES. FOR EXAMPLE, POST-MORTEM BRAINS OF SCHIZOPHRENIC AND PARKINSON PATIENTS HAVE ALTERED LEVELS OF DOPAMINE RECEPTORS, A CONSEQUENCE OF DOPAMINE DRUG THERAPIES AND/OR THE DISEASE STATES. ALTHOUGH THE END STATUS OF DOPAMINE RECEPTOR MODULATION BY DRUG TREATMENT HAS BEEN DESCRIBED, LITTLE IS KNOWN ABOUT THE CELLULAR MECHANISMS OF DRUG-INDUCED RECEPTOR ADAPTIVE PROCESSES. IN PHASE I OF THE PROJECT WE PROPOSE TO SYNTHESIZE FLUORESCENT PROBES AS A NOVEL APPROACH TO MONITORING DOPAMINE RECEPTOR MOBILITY IN BRAIN MEMBRANES. FLUORESCENT COMPOUNDS WILL BE COUPLED TO DOPAMINE AGONISTS (THERAPEUTIC DRUGS FOR PARKINSON'S DISEASE) AND ANTAGONISTS (THERAPEUTIC AGENTS FOR SCHIZOPHRENIA). WE WILL TEST THE AFFINITY AND SELECTIVITY OF THESE COMPOUNDS FOR DOPAMINE RECEPTORS. NEURAL MEMBRANES AT VARIOUS LEVELS OF TISSUE ORGANIZATION WILL CONSEQUENTLY BE EXPOSED TO THE FLUORESCENT PROBE, PHOTOBLEACHED BY LASER BEAM, AND THE RECOVERY OF FLUORESCENCE WILL BE MONITORED BY FLUORESCENT MICROSCOPY. THESE COMPOUNDS WILL PROVIDE MUCH NEEDED INFORMATION ON THE MOBILITY OF DOPAMINE RECEPTORS OCCUPIED BY THERAPEUTIC DRUGS.