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.