Nitric oxide synthase inhibition by dimaprit and dimaprit analogues.

1. The similarity in molecular structure between the histamine H2-agonist dimaprit (3-dimethylamino-propyl-isothiourea) and the endogenous nitric oxide synthase (NOS) substrate L-arginine prompted us to study the effect of dimaprit and some dimaprit analogues on NOS activity. Dimaprit and some of its analogues were tested in an in vitro assay which measures the conversion of [3H]-L-arginine to [3H]-L-citrulline. Dimaprit inhibits rat brain NOS (nNOS) concentration dependently with an IC50 of 49+/-14 microM. 2. Removal of one or both of the methyl groups from the non-isothiourea nitrogen of dimaprit improved nNOS inhibitory properties. Aminopropylisothiourea is the most potent compound (IC50 = 4.1+/-0.9 microM) of the series followed by methylaminopropylisothiourea (IC50 = 7.6 +/- microM). 3. The observed effect of aminopropylisothiourea and methylaminopropyl-isothiourea are probably not due to the compounds themselves but to the corresponding mercaptoalkylguanidines, rearrangement products formed in aqueous solutions. This hypothesis is strengthened by the finding that aminobutylisothiourea is not active since a rearrangement to mercaptobutylguanidine does not 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 H2-agonist and H3-agonist activity of this compound.