Niric Oxide (NO) is a free radical which plays an important role in cellular signalling in mammals. NO is involved in the regulation of vascular tone, modulation of platelet adhesion, whereas in the central nervous system NO isgenerated following the activation of the ionotropic and the metabotropic receptors of the excitatory aminoacid. Larginine has been shown to be obligatory for the formation of the NO. Substances capable of antagonising the effect of NO could be suitable in the therapy of some forms in which there is an excessive vasodilator response or over-activation of the central excitatory circuits. A series of new arginine derivatives named MCS1, MCS2, MCS3, MCS4, MCS5, MCS6, MCS7 have been synthetized and their action on the NO synthase (NOS) has been tested. The NOS activity has been tested in homogenates of both human umbilical endothelial cells (HUVEC) and rat brain, by evaluating the conversion of 14C-L-arginine in 14C-L-citrulline in the presence and absence of scalar concentration of MCS compounds (10 μM- 100 μM). In both HUVEC and rat brain, the 14C-L-citrulline formation was completely inhibited by MCS3, MCS4, MCS5, MCS6 and MCS7 at the 100 μM concentration; MCS1 and MCS2 inhibited the NOS activity in the rat brain, but failed to inhibit NOS activity in HUVEC, MCS3, MCS4, MCS5, MCS6 were equiactive on the neuronal NOS and endotelial NOS whereas MCS7 was more active in inhibiting both. The results of the present study suggest that some arginine derivative compounds are able to block the NOS. Some of these compounds are able to inhibit the NOS production at both endothelial and neuronal level, whereas others are active only on one substrate. In particular, MCS1, MCS2 and MCS7 are relatively selective for neuronal NOS whereas MCS7 is also active on endothelial NOS.