PART 1: SYNTHESIS OF IRREVERSIBLE INHIBITORS OF ALDOSE REDUCTASE WITH SUBSEQUENT DEVELOPMENT OF A CARBON-13 NMR PROTEIN PROBE. PART 2: SYNTHESIS OF SELENIUM ANALOGS OF DOPAMINE AS POTENTIAL DOPAMINE RECEPTOR AGONISTS.

摘要

Part I. The enzyme aldose reductase converts glucose into sorbitol using NADPH as a cofactor. Sorbitol accumulation in various tissues is believed to play a major role in the development of debilitating complications of diabetes; thus, much effort has been directed toward the preparation of aldose reductase inhibitors. The inhibitors known to date are believed to interact at a common inhibitor binding site. In an effort to probe this binding site, we have synthesized various affinity and photoaffinity labels of the enzyme as potential irreversible inhibitors. Of the compounds prepared, the most active are the isothiocyanate and azide analogs of the reversible aldose reductase inhibitor alrestatin. Compounds synthesized based upon the structure of the reversible aldose reductase inhibitor sorbinil possessed poor irreversible inhibition activity and, combined with data from the alrestatin analogs, help to provide information about the location of a nucleophile on the aldose reductase inhibitor site.;Part II. Dopamine is perhaps the most studied neurotransmitter of the central nervous system. Research in our laboratory over the years has focused on answering two fundamental questions regarding the interaction of dopamine with its receptor. First, can the concept of bioisosterism be applied to dopamine agonists? Secondly, what is the actual molecular species of dopamine which interacts with the dopamine receptor?;In an effort to answer these questions, methyl selenide and dimethyl selenonium analogs of dopamine have been synthesized. The charged selenonium salt is active as a dopamine agonist while the uncharged selenide is inactive. This suggests that the charged form of dopamine is optimum for receptor interaction and indicates that bioisosteric replacement can be applied to the development of dopamine agonists. In addition, other selenium analogs of dopamine, possessing bulkier groups on selenium, have been synthesized to examine the extent of bulk tolerance on the dopamine receptor.;The potency of the alrestatin isothiocyanate prompted us to examine the possibility that isothiocyanates enriched with carbon-13 could be used as carbon-13 NMR protein probes. Toward this end, a synthesis of carbon-13 enriched phenylisothiocyanate has been developed. This reagent has been successfully utilized to study peptides via carbon-13 NMR spectroscopy.