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.
