Inhibition of neuronal nitric oxide synthase (NOS) appears to be a viable approach for the blockage of neurotoxicity resulting from stroke, Huntington, and Alzheimer diseases, and in the treatment of long-term depression and long-term potentiation. Seven general areas will be pursued directed at 1) synthesis and evaluation of conformationally-rigid peptidomimerics of Nomega-nitroarginine-Dbu and Nomega-nitroarginine-ornithine, our potent and selective nitric oxide synthase (NOS) inhibitors; 2) synthesis and evaluation of conformationally-rigid peptidomimetics of Nomega-nitroarginine-descarboxamides 3) synthesis and evaluation of peptidomimetics containing amide bond isosteres; 4) site-directed mutagenesis of groups that may bind to the sidechain amino group; 5) synthesis and evaluation of compounds to test the function of the nitro group in inhibition of NOS; 6) mechanisms of inactivation of NOS by known inactivators; and 7) X-ray crystal structures of inhibitor complexes with NOS and molecular modeling. The first series of compounds are 3- and 4-aminoproline- and 4- and 5-amino-2-pipecolic acid analogues of the selective dipeptides. Another series of compounds contains cyclic- and heterocyclic diamines, which will be substituted for straight-chain analogues we have made. Several series of compounds with isosteres of the amide bond of our selective inhibitors will be made containing beta- and gamma hydroxyethylene, ketomethylene, alkene, and alkane isosteres with both straight-chain and conformationally rigid (cyclic, aromatic, heteroaromatic) amines. To test our hypothesis for the function of the nitro group in selectivity, heteroaromatic analogues will be synthesized and evaluated for NOS inhibition. Previously we studied the inactivation of NOS by Nomega allylarginine and N-iminoethylomithine (MO). Structural and mechanistic studies will be carried out to support or modify our hypotheses for the inactivation mechanisms. Mechanisms of other compounds that appear to be structurally related to MO will be tested. A collaboration has been set up to carry out X-ray crystallography of our most potent and selective inhibitors bound to NOS to identify the important binding interactions, and the coordinates will be used for computer modeling studies using 3D-QSAR, DOCK, and GrowMol programs to identify new leads and modify the current ones.
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