AFFINITY LABELS FOR DOPAMINE RECEPTORS

DYSFUNCTION OF BRAIN DOPAMINE (DA) RECEPTORS HAS BEEN IMPLICATED IN ENDOCRINE, NEUROLOGICAL, AND PSYCHIATRIC DISORDERS. DETAILED PHARMACOLOGICAL EVALUATION AND THE STUDY OF BIOCHEMICAL FUNCTION OF THE DA RECEPTORS HAVE BEEN MADE POSSIBLE BY THE SYNTHESIS OF HIGH-AFFINITY LIGANDSTHAT ARE SELECTIVE FOR EACH OF THE RECEPTOR SUBTYPES. AFFINITY LABELS, DRUG MOLECULES THAT BIND SPECIFICALLY AND IRREVERSIBLY TO A PARTICULAR BIOLOGICAL SYSTEM, ARE IMPORTANT TOOLS IN ENZYME, HORMONE, AND NEUROTRANSMITTER RECEPTOR RESEARCH. AFFINITY-LABELING EXPERIMENTS WITH NEUROTRANSMITTER RECEPTORS HAVE PROVIDED A WEALTH OF INFORMATION REGARDING THE STRUCTURE AND BIOCHEMICAL PROPERTIES OF MEMBRANE-BOUND RECEPTORS WITH ADRENERGIC, OPIOD, AND STEROID RECEPTORS. PHASE I OF THIS PROGRAM INVOLVES THE SYNTHESIS AND PHARMACOLOGICAL CHARACTERIZATION OF AFFINITY AGENTS THAT WILL COVALENTLY BOND AT A REACTIVE SITE AT D1 OR D2 SITES. THE REACTIVE GROUPS ATTACHED TO THESE SELECTIVE LIGANDS COVER A RANGE OF REACTIVITY, INCLUDING MICHAEL ACCEPTOR GROUPS AND ALKYLATING AGENTS USED SUCCESSFULLY IN OTHER RECEPTOR SYSTEMS. COMPOUNDS PROPOSED FOR SYNTHESIS AND PHARMACOLOGICAL EVALUATION INCLUDE THE FOLLOWING AGENTS: (1) ANALOGS OF SKF 38393 AS D1 AGONISTS AND THEIR CONGENERS WITH ALKYLATING MOIETIES AS D1 ANTAGONISTS; (2) ANALOGS OF SCH 23390 AS D1 ANTAGONISTS; (3) ANALOGS OF THE AMINOTETRALIN, PPHT, AS D2 AGONISTS AND THEIR CONGENERS WITH ALKYLATING MOIETIES AS D2 ANTAGONISTS; AND (4) SPIPERONE ANALOGS AS D2 ANTAGONISTS.