SELECTIVE-INHIBITION OF NEURONAL NITRIC-OXIDE SYNTHASE BY N-OMEGA-NITROARGININE-CONTAINING AND PHENYLALANINE-CONTAINING DIPEPTIDES AND DIPEPTIDE ESTERS

A series of N-omega-nitroarginine (Arg(NO2))-and phenylalanine-contain ing dipeptides and dipeptide esters were synthesized as potential sele ctive inhibitors of neuronal nitric oxide synthase (nNOS). All of the dipeptides and dipeptide esters are competitive inhibitors of nNOS, ma crophage nitric oxide synthase (iNOS), and endothelial nitric oxide sy nthase (eNOS), except for the ones that contain D-Arg(NO2) (8-10, 12, 13), which are uncompetitive inhibitors of iNOS but competitive inhibi tors of nNOS and eNOS. None of the dipeptides or dipeptide esters test ed (1, 2, 12, 13) exhibited time-dependent inhibition of any of the NO S isoforms, unlike N-omega-nitro-L-arginine itself, which does, althou gh it is reversible. The order of the amino acids in the dipeptide or dipeptide ester is important to selectivity, and the selectivity depen ds on the chirality of the amino acids. In the case of the correspondi ng benzyl esters (5 vs 6), both dipeptides favor iNOS over nNOS and eN OS inhibition. All of the dipeptide methyl esters containing a D-amino acid, however, exhibit an inhibitary preference for nNOS over iNOS an d eNOS. The most impressive selectivities observed are 1800- and 800-f old for 12 and 13, respectively, in favour of nNOS over iNOS, unfortun ately, the selectivities of these compounds for nNOS over eNOS are onl y 2.5 and 5.3, respectively.