Synthesis of glycosyl derivatives as dopamineprodrugs: interaction with glucose carrier GLUT-1

Abstract

Glucosyl dopamine (DA) derivatives may represent a new class of DA prodrugs that would interact with glucose transporter GLUT-1, present in the blood–brain barrier, and generate DA in the brain. Therefore, compounds bearing the sugar moiety linked to either the amino group or the catechol ring of DA through amide, ester, carbamate, peptide or glycosidic bonds were synthesized. The behavior of the compounds as prodrugs was monitored in different media and the affinity of the glycoconjugates for the glucose carrier GLUT-1 using human erythrocytes was also studied. Most of the compounds were markedly stable in buffer and plasma, and several compounds released DA when incubated with brain extracts and the rate was related to the bond linking DA with glucose. The new glucosyl conjugates substituted at the C-6 position of the sugar were more potent inhibitors of glucose transport when compared to C-1 and C-3 substituted derivatives. This work provides structure–activity information about the interaction of substituted glucose with the GLUT-1 transporter.