Norepinephrine N-methyltransferase inhibition by benzamidines, phenylacetamidines, benzylguanidines, and phenylethylguanidines.

Norepinephrine N-methyltransferase (NMT) from rabbit adrenal glands was inhibited by benzylamine and phenethylamine analogs in which the nitrogen was replaced by an amidino or guanidino group. Mono and dichloro derivatives of benzamidines, phenylacetamidines, benzylguanidines, and phenethylguanidines were studied. The two most potent NMT inhibitors among the compounds examined were 2,3-dichlorobenzamidine and 3,4-dichlorophenylacetamidine, with pI50 values of 5.55 and 5.36, respectively. These inhibitors were reversible and were competitive with norepinephrine as the variable substrate. They inhibited NMT from human, rat, and bovine adrenal glands but were slightly less effective against those enzymes than against the rabbit adrenal enzyme. In exercised rats, 2, 3-dichlorobenzamidine had no significant effect on adrenal catecholamine levels. 3,4-Dichlorophenylacetamidine slightly reduced epinephrine levels in the adrenal glands of exercised rats, but the effect may have been due to release rather than inhibition of synthesis, since heart norepinephrine levels were also reduced significantly by that agent (which is from a chemical series known to release catecholamines). Thus, whereas these compounds are reasonably potent inhibitors of NMT in vitro, they apparently are not effective in blocking enzyme activity in vivo.