Nitric oxide synthase inhibition by dimaprit and dimaprit analogues

1 The similarity in molecular structure between the histamine H-2-agonist d imaprit (3-dimethylamino-propyl-isothiourea) and the endogenous nitric oxid e synthase (NOS) substrate L-arginine prompted us to study the effect of di maprit and some dimaprit analogues on NOS activity. Dimaprit and some of it s analogues were tested in an in vitro assay which measures the conversion of [H-3]-L-arginine to [H-3]-L-citrulline. Dimaprit inhibits rat brain NOS (nNOS) concentration dependently with an IC50 of 49 +/- 14 mu M 2 Removal of one or both of the methyl groups from the non-isothiourea nitr ogen of dimaprit improved nNOS inhibitory properties. Aminopropylisothioure a is the most potent compound (IC50 = 4.1 +/- 0.9 mu M) of the series follo wed by methylaminopropylisothiourea (IC50 = 7.6 +/- mu M). 3 The observed effect of aminopropylisothiourea and methylaminopropyl-isoth iourea are probably not due to the compounds themselves but to the correspo nding mercaptoalkylguanidines, rearrangement products formed in aqueous sol utions. This hypothesis is strengthened by the finding that aminobutylisoth iourea is not active since a rearrangement to mercaptobutylguanidine does n ot occur. 4 Remarkably, nitrosylation of the isothiourea group of dimaprit decreases nNOS inhibitory activity, while nitrosylation of the guanidine analogue of dimaprit increases the inhibition of nNOS activity. 5 The pharmacological profile of dimaprit includes inhibition of nNOS. The nNOS inhibitory activity occurs in the same concentration range as the H-2- agonist and H-3-agonist activity of this compound.