Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by
different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including
neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an
overproduction of NO is related with several disorders as Alzheimer’s disease, Huntington´s disease and the amyotrophic
Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as
NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum,
and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative
families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment
of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed
SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors.
The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds
show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid
methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both
compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS)
observed in a MPTP model of Parkinson´s disease.