Improvement of peptide delivery to brain by chemical modification :

[D-Ala²] Leu-enkephalin conjugated with 1-adamantane

Abstract

An ester compound (Ada-Enk) of [D-Ala²] Leu-enkephalin(Enk) with 1-adamantanol was evaluated as a prodrug for the improved brain delivery using rats as the experimental animal. The tissue-to-plasma concentration ratio (Kp) of Ada-Enk at steady state during the intravenous infusion was 4.5 times larger than that of Enk, indicating the improved delivery to the brain. The distribution of Ada-Enk to the other organs was also increased in comparison with Enk, but the degree of the enhanced distribution was much higher in the brain. The distribution of Ada-Enk was similar in all the regions in the brain. In addition, Enk was found in the brain during the intravenous infusion of Ada-Enk. The in vitro metabolic study showed that Ada -Enk was metabolized in both plasma and brain while Enk was formed in the brain homogenates much more than in the plasma.