Peptidomimetic isoform selective nNOS inhibitors

T he discovery of the cyclic nucleotides 3',5'cyclic monophosphate (cAMP, Prod. No. A 9501, A 4137) and guanosine 3',5'-cyclic monophosphate (cGMP, Prod. No. G 7504, G 6129) led to the first formulation of the second messenger concept. These cyclic nucleotides are now known to be ubiquitous intracellular second messengers that mediate the response of cells to a variety of extracellular stimuli through the activation of cyclic nucleotide-dependent protein kinases, ion channels, GTP-exchange factors and their downstream effector systems [1]. The amplitude and duration of cAMP and cGMP signals are controlled by their rates of synthesis by adenylyl and guanylyl cyclases, respectively, and their degradation by 3’,5'-cyclic nucleotide phosphodiesterases (PDEs) (Figure 1). PDEs, identified shortly after the discovery of cAMP and cGMP, are a large superfamily of enzymes that hydrolyze the 3' phosphodiester bond in cAMP or cGMP to form the corresponding 5'-nucleotide