New systems for the specific delivery and sustained release of dopamine to the brain

The present paper reports the synthesis of the chemical delivery system 5 and dopamine (DA) prodrug 6 as well as their application for the specific delivery and sustained release of DA to the rat brain. The ability of 5 and 6 to penetrate the blood-brain barrier (BBB) and release DA into the central nervous system (CNS) was assessed by comparing, on a molar basis, the behavioural effects produced by DA itself and the above compounds, when centrally or peripherally administered in conscious rats. When intravenously injected, both derivatives 5 and 6 elicited vacuous chewing behaviours comparable with those induced by intracerebroventricular (icy) injection of the parent drug. These results suggest that 5 and 6 are able to cross the BBB and enter the CNS, releasing DA. Furthermore, a long lasting effect was observed for the tripivaloyl-derivative 6, likely due to a slower release of DA following from an increased resistance of the sterically hindered pivaloylamide group to enzymatic hydrolysis. It must be pointed out that the cu-adrenergic 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.