NEW SYSTEMS FOR THE SPECIFIC DELIVERY AND SUSTAINED-RELEASE OF DOPAMINE TO THE BRAIN

The present paper reports the synthesis of the chemical delivery syste m 5 and dopamine (DA) prodrug 6 as well as their application for the s pecific delivery and sustained release of DA to the rat brain. The abi lity of 5 and 6 to penetrate the blood-brain barrier (BBB) and release DA into the central nervous system (CNS) was assessed by comparing, o n a molar basis, the behavioural effects produced by DA itself and the above compounds, when centrally or peripherally administered in consc ious rats. When intravenously injected, both derivatives 5 and 6 elici ted vacuous chewing behaviours comparable with those induced by intrac erebroventricular (icy) injection of the parent drug. These results su ggest that 5 and 6 are able to cross the BBB and enter the CNS, releas ing DA. Furthermore, a long lasting effect was observed for the tripiv aloyl-derivative 6, likely due to a slower release of DA following fro m an increased resistance of the sterically hindered pivaloylamide gro up to enzymatic hydrolysis. It must be pointed out that the cu-adrener gic effect (piloerection) observed after DA was peripherally injected was not observed after systemic administration of the compounds 5 and 6, This finding may indicate that neither the chemical delivery system 5 nor the prodrug 6 release free DA at bioactive concentrations at a peripheral level.