NITRIC-OXIDE SYNTHASE INHIBITORS - FUTURE THERAPIES FOR CNS DISORDERS

Nitric oxide (NO) is a messenger that is involved in many physiologica l events including host defence, vascular tone and neurotransmission. It plays a role in many nervous system functions including synaptogene sis during brain development, synaptic plasticity associated with lear ning and memory, and regulation of cerebral blood flow. NO is produced from at least 3 different NO synthase (NOS) isoforms: neuronal NOS (t ype-1; nNOS), immunological NOS (type-2; iNOS) and endothelial NOS (ty pe-3; eNOS). Under conditions of excessive formation, NO may elicit ne uropathological changes. For example, excess NO from nNOS has been imp licated in neuronal damage associated with stroke, excitotoxins, mitoc hondrial toxins and 1-methyl-4-phenyI-1,2,3,6-tetrahydropyridine (MPTP ). Activation of iNOS may play a role in the pathogenesis of multiple sclerosis and severe AIDS dementia, while derangements in NO formation from eNOS may play a role in the pathogenesis of migraine headaches. Thus, the development of specific NO inhibitors has become a major cha llenge. Selective inhibitors are beginning to be developed for the var ious isoforms of NOS, which raises the possibility that medicinal chem ists will be able to develop well tolerated and selective NOS inhibito rs that may be used for the treatment of CNS disorders that are due to derangements of NO.