1, 2-dihydroisoquinoline-N-acetic acid derivatives as new carriers for brain-specific delivery II: delivery of phenethylamine as model drug.

Abstract

N-alkyloxycarbonylmethyl-1, 2-dihydroisoquinolin-4-carboxylic acid derivatives 7a-c synthesized as new carriers for brain specific delivery. The design of the carrier systems are based on sequential hydrolysis at the acetic acid ester group linked to dihydroisoquinoline nitrogen followed by ring oxidation and formation of quaternary isoquinolinium derivatives which are then hydrolyzed to release the drug. Once the carrier system is administered, a sequential enzymatic process will take place resulting in significant increase in its rate of oxidation, the key factor in brain specific delivery. The chemical stability of the synthesized carrier system was investigated in aqueous buffer solutions and ferricyanide reagent and proofed to be quite stable against hydration and oxidation during formulation and storage. Furthermore, enzymatic stability was also investigated in 80 % human plasma and 20 % rabbit brain homogenate. Both oxidation and hydrolysis were found to take place; however, hydrolysis was the major route. In vivo distribution of the ethyl ester derivative 7b studied in rats and showed that the concentration of the quaternary product is increasing in the brain and cleared from blood with time.