New folate antagonists are required which do not elicit a resistant response in the target cells, and which are able to combat a wider range of tumors. The molecular basis of specificity of pteridines and related compounds is being determined so that more effective anti-folates may be developed which are specific for dihydrofolate reductase, and which do not interfere with other pteridine utilizing enzymes. Series of substituted pteridines and pyrimidines are being studied as cofactors and inhibitors of the three aromatic amino acid hydroxylase. Each of these enzymes has a specific requirement for a pteridine cofactor, tetrahydrobiopterin, and is involved in the biosynthesis of the neurotransmitters, serotonin, dopa, and nor-epinephrine. The effects of these compounds are also being assessed on dihydropteridine reductase, the enzyme which in vivo regenerates tetrahydrobiopterin. Any pteridine-like drug aimed at dihydrofolate reductase, including pyrimidines as recently demonstrated (Bailey and Ayling, Biochem. Biophys. Res. Comm. 85, 1614-21. 1978), has the potential to interfere with these tetrahydrobiopterin dependent neurotransmitter synthesizing systems. The structure action relationships determined in this work will aid in the interpretation of drug screening, and will provide the information necessary to make selective inhibitors of dihydrofolate reductase.