Relationship between structure and inhibitory effect of arginine analogues on neuronal nitric oxide synthase activity

Abstract

Since nitric oxide (NO) is synthesized by nitric oxide synthase (NOS) from L-arginine (Arg) which has an amidino group in its molecule, we examined the effect of 29 kinds of Arg analogues on neuronal NOS (nNOS) activity in the rat brain. None of the Arg analogues acted as a substrate for nNOS. Diamidinocystamine, hirudonine, and guanethidine inhibited nNOS activity to 67.3%, 64.2% and 74.1%, respectively, but their inhibitory efficiency was lower than NG-monomethyl-L-arginine (to 36.5%) which is a well known NOS inhibitor. Dimethylguanidine and N-benzoylguanidine also significantly inhibited nNOS activity to 88.0% and 90.7%, respectively. Whereas almost all of the NOS inhibitors previously reported were synthesized by substituting the amidino nitrogen of Arg, none of these new inhibitors were substituted at this position. Furthermore, hirudonine, which is a naturally occurring compound, was thought to act as an agonist at polyamine binding site of the N-methyl-D-aspartate type of glutamate receptor complex. It is also interesting that guanethidine, an antihypertensive agent, inhibit nNOS activity. These new drugs are useful for the investigation not only of the chemical nature of nNOS but also of the physiologic function of NO.

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

“…Many modifications made to l -arginine at positions other than the guanidine moiety (e.g., introduction of aromatic groups, sulfonic acids, and heterocycles) resulted in compounds that are neither NOS inhibitors nor substrates, 77 but many arginine derivatives alkylated on the guanidine group possess NOS inhibitory activity. Hibbs 78 first described N ω -methyl- l -arginine ( l -NMA, 3 ) as a NOS inhibitor.…”

“…73 Nonetheless, these simple nitroarginines are nonselective NOS inhibitors, and while 1 has around 300-fold selectivity in favor of nNOS over iNOS, 74 nitroarginines cause severe hypertension when administered to animals as a result of potent inhibition of eNOS as well. 76 Many modifications made to L-arginine at positions other than the guanidine moiety (e.g., introduction of aromatic groups, sulfonic acids, and heterocycles) resulted in compounds that are neither NOS inhibitors nor substrates, 77 but many arginine derivatives alkylated on the guanidine group possess NOS inhibitory activity. Hibbs 78 first described N o -methyl-L-arginine (L-NMA, 3) as a NOS inhibitor.…”

“…Like inhibitors that bind at the active site of NOS and additionally interact with H 4 B, imidazole-based inhibitors that bind competitively at heme and also interact with the calmodulin (CaM) binding site are known. Miconazole (76), ketoconazole (77), and clotrimazole (78) are imidazole-containing antifungal agents that showed competitive inhibition of L-citrulline formation in bovine nNOS with K i values of 7, 44, and 19 mM, respectively, while they also showed calmodulin-dependent competitive inhibition of cytochrome c reductase activity of nNOS. 193 Although these compounds show selectivity over iNOS, there was no selectivity between nNOS and eNOS.…”