STRUCTURE-ACTIVITY-RELATIONSHIPS OF ARGININE ANALOGS ON NITRIC-OXIDE SYNTHASE ACTIVITY IN THE RAT-BRAIN

Nitric oxide (NO) is synthesized by nitric oxide synthase (NOS) from L -arginine (Arg) which has a guanidino group in its molecule. We examin ed the effect of 23 different Arg analogues on NOS activity in the rat brain. Though homoarginine, epsilon-guanidinocaproic acid and canavan ine act as substrates of NOS, production of NO from them was lower tha n that from Arg. alpha-Guanidinoglutaric acid (2-GGA) and arcaine inhi bited NOS activity at levels equal to N-G-monomethyl-L-arginine (MeArg ), a well known NOS inhibitor. Though almost all previously reported N OS inhibitors were synthesized by substituting the guanidino nitrogen of Arg, the guanidino nitrogens of arcaine and 2-GGA were not substitu ted. Furthermore, 2-GGA is a known endogenous convulsant in mammals, a nd arcaine, which was isolated from a marine mollusc, is also a convul sive substance. Hence, 2-GGA and arcaine will be excellent drugs to in vestigate not only the chemical nature of NOS but also the physiologic function of NO.