The goal of this proposal is to develop a means of treating Parkinson's disease and related neurological disorders caused by deficiency in catecholamine neurotransmitters. Tyrosine hydroxylase, the rate limiting enzymes in the synthesis of the catecholamines, is regulated by the availability of its cofactor, tetrahydrobiopterin (BH4), the only known function of which, in mammals, is to facilitate enzymatic hydroxylation of the three aromatic amino acids. A variety of neurological disorders including Parkinson's Disease, Alzheimer's disease, Shy-Drager's syndrome, Steel-Richardson's syndrome, Huntington's chorea, dystonia, and some forms of depression are associated with decreased levels of BH"""""""" with a consequent decrease in the rate of biosynthesis of the products. This suggested that such disorders might be alleviated by administration of BH4. Trials with BH4 in patients with Parkinson's disease, dystonia or depression, although resulting in variable success, indicate the potential of cofactor therapy for these disorders. A major set-back has been the very high doses required to produce a clinical response. Our own results, as well as those of others, indicate that this is due to the instability and poor absorbtion and penetration of tetrahydrobiopterin into the brain. Thus, cofactor analogs are required with improved pharmacokinetics properties. The development of such compounds is the goal of this proposal. This will be approached by a series of studies beginning with the synthesis and chemical characterization of specifically substituted tetrahydropterins. These will be tested for cofactor activity and specificity with the three aromatic amino acid hydroxylases, and their quinoid dihydro-forms as substrates for the cofactor regenerating enzyme, dihydropteridine reductase. On the basis of in vitro testing, candidates will be selected for in vivo experiments. The pharmacokinetics parameters will be determined. and an animal model will be used to assess dopaminergic activity in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS026662-01
Application #
3412644
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
Ayling, J E; Bailey, S W; Boerth, S R et al. (2000) Hyperphenylalaninemia and 7-pterin excretion associated with mutations in 4a-hydroxy-tetrahydrobiopterin dehydratase/DCoH: analysis of enzyme activity in intestinal biopsies. Mol Genet Metab 70:179-88
Rebrin, I; Thony, B; Bailey, S W et al. (1998) Stereospecificity and catalytic function of histidine residues in 4a-hydroxy-tetrahydropterin dehydratase/DCoH. Biochemistry 37:11246-54
Bailey, S W; Ayling, J E (1997) Total chemical synthesis of chirally pure (6S)-tetrahydrofolic acid. Methods Enzymol 281:3-16
Rebrin, I; Bailey, S W; Boerth, S R et al. (1995) Catalytic characterization of 4a-hydroxytetrahydropterin dehydratase. Biochemistry 34:5801-10
Rebrin, I; Bailey, S W; Ayling, J E (1995) Activity of the bifunctional protein 4a-hydroxy-tetrahydropterin dehydratase/DCoH during human fetal development: correlation with dihydropteridine reductase activity and tetrahydrobiopterin levels. Biochem Biophys Res Commun 217:958-65
Bailey, S W; Boerth, S R; Dillard, S B et al. (1993) The mechanism of cofactor regeneration during phenylalanine hydroxylation. Adv Exp Med Biol 338:47-54
Waymire, J C; Ayling, J E; Craviso, G L (1993) Nicotinic cholinergic regulation of tetrahydrobiopterin levels in bovine adrenal chromaffin cells. Adv Exp Med Biol 338:235-8
Bailey, S W; Dillard, S B; Ayling, J E (1991) Role of C6 chirality of tetrahydropterin cofactor in catalysis and regulation of tyrosine and phenylalanine hydroxylases. Biochemistry 30:10226-35