PubMed · 9172519
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K Azuma, M Irahara, T Aono. 1997. [L-dopa and dopamine loading test].. https://pubmed.ncbi.nlm.nih.gov/9172519/
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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.
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Although changes in nucleotide sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G+C content of the third codon positions from the isochoric G+C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being 'silent', altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced up-regulation of DRD2 expression. 1101A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141C Ins/Del and TaqI 'A' variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance.