Inhibition of nitric oxide (NO) synthase appears to be a viable approach for the blockage of neurotoxicity resulting from stroke, Huntington, and Alzheimer diseases, in the treatment of septic shock, long-term depression, and long-term potentiation, in protection against immune complex-induced vascular injury, and in the treatment of priapism. Five areas of research will be pursued directed at the design of new isoform-selective inhibitors, the design and mechanism of inactivation of new inactivators of nitric oxide synthase (NOS), and at one question of the catalytic mechanism of the enzyme. One class of new isoform-selective inhibitors is the N omega -alkyl-L-arginines; a series of these derivatives, based on the high selectivity the investigators recently found for N omega -propyl-L-arginine, will be synthesized and tested as inhibitors of the three isoforms of NOS. Another series proposed as isoform-selective inhibitors includes dipeptide and dipeptide esters, based on the high selectivity we found for the D-isomers of nitroarginine-containing peptides and peptide esters. Histidine- and N omega -alkyl-L-arginines- containing dipeptides and -dipeptide esters also will be made and tested for isoform selectivity. New inactivators proposed are analogs of N omega -allyl-L-arginines containing methyl and fluorine substituents to determine the effects of these substituents on the reactivity of the inactivator, on the partition ratio, and on isoform selectivity. Conformationally-rigid analogs of N omega -allyl-L-arginines will be prepared to determine conformational effects on inactivation and selectivity. Other potential inactivators include derivatives of N omega -propargyl-L-arginines, N-propargylguanidine, N-propargylornithine, and heterocyclic compounds containing an N-imidazolyl ornithine and the corresponding chlorinated analog. 2,2-Dichloro-1-iminoethyl-L-ornithine, the dichlorinated analog of the potent inactivator, N5-(1-iminoethyl)-L-ornithine, also will be prepared and tested. On the basis of the observation that hydrogen atom abstraction can occur at the alpha methylene of N omega - substituted arginines, N omega -cyclopropylmethyl-, 2-phenylcyclopropylmethyl-, and cubylmethyl analogs of arginine will be synthesized and tested. An attempt will be made to differentiate a hydrogen atom abstraction mechanism from an electron transfer mechanism for the oxidation of N omega -hydroxy-L-arginine by NOS.
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