RELATIONSHIP BETWEEN STRUCTURE AND INHIBITORY EFFECT OF ARGININE ANALOGS ON NEURONAL NITRIC-OXIDE SYNTHASE ACTIVITY

Since nitric oxide (NO) is synthesized by nitric oxide synthase (NOS) from L-arginine (Arg) which has an amidino group in its molecule, we e xamined 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 subst rate for nNOS. Diamidinocystamine, hirudonine, and guanethidine inhibi ted nNOS activity to 67.3%, 64.2% and 74.1%, respectively, but their i nhibitory efficiency was lower than N-G-monomethyl-L-arginine (to 36.5 %) which is a well known NOS inhibitor. Dimethylguanidine and N-benzoy l-guanidine 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. Furt hermore, hirudonine, which is a naturally occurring compound, was thou ght to act as an agonist at polyamine binding site of the N-methyl-D-a spartate type of glutamate receptor complex. It is also interesting th at guanethidine, an antihypertensive agent, inhibit nNOS activity. The se new drugs are useful for the investigation not only of the chemical nature of nNOS but also of the physiologic function of NO.