SYNTHESIS AND EVALUATION OF A REDOX CHEMICAL DELIVERY SYSTEM FOR BRAIN-ENHANCED DOPAMINE-CONTAINING AN ACTIVATED CARBAMATE-TYPE ESTER

A chemical delivery system (CDS) for enhanced delivery of dopamine to brain tissue, based on a dihydropyridine double left right arrow pyrid inium salt redox system, was modified to include an activated carbamat e ester. The dihydronicotinate moiety was chemically attached to the a mino group of dopamine (DA) by acylation with chloroethyl chloroformat e, followed by condensation with sodium nicotinate under mild conditio ns. The product was selectively N-alkylated at the pyridine ring and s ubjected to regioselective reduction to the corresponding 1,4-dihydrop yridine derivative, DA-CDSac. In vitro stability of the new compound w as studied in phosphate buffers at mild acidic, physiological, and mil d alkaline pH values. Oxidation studies showed facile conversion of th e dihydronicotinate, DA-CDSac, is readily converted to the correspondi ng quaternary salt, both chemically and enzymatically. In vivo studies in rats did not detect sustained increases in brain levels of the qua ternary salt after i.v. dosing with DA-CDSac. However, the new CDS app eared to change spontaneous locomotor activity in rats after i.v. admi nistration which may be due to altered central DA neuronal activity.