Although diseases characterized by neuronal damage and degeneration have an enormous public health and economic impact, treatment of these disorders is often limited to palliative care and slowing of symptom progression. Therefore, drugs that stop or slow neurodegeneration are highly desirable. One emerging target is neuronal nitric oxide synthase (nNOS), an enzyme that produces the signaling molecule NO. Although required for normal neuronal function, high levels of NO have been implicated in chronic neurodegenerative pathologies (such as Parkinson's disease) as well as stroke, migraines, and other disorders. Ergo, inhibition of this enzyme could be desirable for treatment of these diseases. Nonetheless, as most nNOS inhibitors mimic the natural substrate L-arginine, their therapeutic practicality is diminished by their excessive polarity and basicity, properties tat cause poor GI uptake and low blood-brain barrier permeability. Additionally, care must be taken to not inhibit the related NOS isoforms eNOS and iNOS, or dangerous side effects could result. The work detailed herein describes several strategies for the design and optimization of bioavailable nNOS inhibitors. First, preliminary data indicates that the N-benzylphenethylamine core is a scaffold that confers potent nNOS activity and ~100-fold isoform selectivity. In Aim 1, grafting a low-pKa heterocycle onto this scaffold via facile synthetic routes should result in a less basic arginine mimetic, and molecular modeling provides evidence that these compounds should bind in a manner similar to reported nNOS inhibitors. Additional optimizations will then be performed on compounds containing effective alternative heterocycles. In Aim 2a, incorporation of halogens and halogen- containing groups, a strategy that has proven effective at enhancing brain penetration for many classes of CNS drugs, will be performed. In Aim 2b, oxetane groups will be introduced into the phenethyl chain to decrease the high pKa of the secondary amines, a modification that is predicted to preserve the hydrogen-bonding capability of these amines without steric encumbrance. Finally, in Aim 3, nNOS and its isoforms will be expressed in E. coli and purified. Compounds will be assayed against the enzymes by the hemoglobin capture assay. In addition, select compounds will be tested in a cell-based nNOS assay, assayed for their metabolic stability, and tested for permeability in a Caco-2 model (to estimate both their GI and CNS uptake).