Selective Neuronal Nitric Oxide Synthase Inhibitors

Abstract

This review includes the non-patent literature up to October 2004 that deals with selective neuronal nitric oxide synthase inhibitors (highest potency is for the neuronal isozyme). Some non-selective inhibitors or selective inducible nitric oxide synthase inhibitors are mentioned if they are related to compounds that are discussed; structures of these compounds generally are not given. In vitro inhibition constants are given either as IC(50) values or as K(i)values. An IC(50) value, the inhibitor concentration that produces 50% inhibition in the presence of a constant concentration of substrate, is obtained by extrapolation of several rate data points to 50% inhibition. K(i) values are derived from several types of plots that relate the concentration of inhibitor with enzyme velocity in the presence of a variety of substrate concentrations [1]. The K(i) value can be estimated from the IC(50) value [2]. Although the two inhibition constants are related, they are not the same; generally, the reported K(i) values tend to be lower than the IC(50) values. If specifics are desired about how the data were collected, then the reader will have to look in the literature cited. No attempt was made to be exhaustive in citing all references related to specific inhibitors; rather, examples of literature references are given for each inhibitor described.

Tonic and Phasic Nitric Oxide Signals in Hippocampal Long-Term Potentiation

“…These results show that there is a tonic low level of NO in hippocampal slices and that the NO synthase isoform at work is unlikely to be nNOS. Moreover, the compound 1400W is a potent inhibitor of iNOS, more so than of nNOS (Alderton et al, 2001;Erdal et al, 2005), but did not affect basal NO-dependent cGMP levels, suggesting that iNOS does not contribute either.…”

“…1400W (1 M) and L-VNIO (0.1 M), as well as a third compound, NPA (1 M), all inhibited the NMDA-stimulated response by 80 -90% but failed to affect acetylcholine-stimulated eNOS activity significantly, although this activity could be abolished by L-NNA (Fig. 1C,D), which inhibits all NO synthases (Alderton et al, 2001;Erdal et al, 2005) and, accordingly, also blocks NMDA-evoked cGMP accumulation in hippocampal slices .…”

“…Much effort has gone into the discovery of selective inhibitors of the different NO synthase isoforms, from which a number of compounds selective for nNOS have now become available (Erdal et al, 2005). An alternative approach of using of nNOSdeficient mice is problematic because of compensation by surviving splice variants (Eliasson et al, 1997).…”

“…An alternative approach of using of nNOSdeficient mice is problematic because of compensation by surviving splice variants (Eliasson et al, 1997). We evaluated three inhibitors chosen to have good selectivity over eNOS in enzyme studies, namely 1400W (also a potent inhibitor of the inducible NO synthase, or iNOS), NPA, and L-VNIO (Alderton et al, 2001;Erdal et al, 2005). To assess their utility, rat hippocampal slices were stimulated with NMDA and the resulting accumulation of cGMP, which depends on nNOS, used to assay NO formation.…”

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

“…13 In an effort to improve PK/PD properties by decreasing their peptidic nature, various small molecule selective nNOS inhibitors have also been reported. 14 The pharmacophore model we adopted for the arginine binding site of the NOS enzyme includes a guanidine isosteric group (amidine group) and a basic amine group, both attached to a central aryl scaffold (indole core) as shown in Figure 1. 4,15 The amidine group makes an important bidentate interaction with the conserved glutamic acid residue to achieve the necessary potency; whereas the basic amine is assumed to provide the nNOS isoform selectivity.…”