Effect of p-chloramphetamine on the inactivation of monoamine oxidase in rat brain by 3-amino-2-oxazolidinone, 2-hydroxyethylhydrazine and pheylisopropylhydrazine.

p-Chloroamphetamine protected against the irreversible inactivation of monoamine oxidase in rat brain and liver by 3-amino-2-oxazolidinone, an agent that leads to monoamine oxidase inhibition through conversion to an active metabolite, probably 2-hydroxyethyl-hydrazine. In contrast, p-chloramphetamine did not protect against the inactivation of monoamine oxidase by 2-hydroxyethylhydrazine itself or by phenylisoprophylhydrazine. The effect on 3-amino-2-oxazolidinone may have been due to interference with its metabolism rather than to occupancy of active sites on monoamine oxidase by p-chloroamphetamine. Some implications of these findings relating ot the use of 3-amino-2-oxazolidinone in evaluating reversible monoamine oxidase inhibitors and to the pharmacological effects of p-chloroamphetamine are discussed.

Procaine hydrochloride as a monoamine oxidase inhibitor: implications for Geriatric therapy.

The results of in vitro experiments showed that inhibition by procaine hydrochloride of monoamine oxidase (MAO) from either rat brain or liver was substrate-dependent. Procaine was more effective in inhibiting serotonin oxidation than phenylethylamine oxidation and had an intermediate effect on tryptamine oxidation. MAO activity in tissue homogenates from rats treated with procaine (150 mg/kg intraperitoneally) was inhibited most in liver, less in heart, and only very slightly brain for a duration of up to 8 hours. Procaine injected in that dose did not alter brain norepinephrine levels and elevated only slightly the brain serotonin levels. It did not protect against the degradation of exogenous radioactive tryptamine in brain. These data confirm and extend prior observations on in vitro inhibition of MAO by procaine and suggest that in high doses procaine may inhibit MAO weakly in vivo. If the reported usefulness of procaine preparations in treating geriatric patients indeed depends upon MAO inhibition, more effective inhibitors would seem to be available.

Influence of PKa on the methylation of arylalkylamines by rabbit lung N-methyltransferase.

Substitution of one or two fluorine atoms on the B carbon of phenethylamine progressively reduced the pKa of the amine and increased its rate of methylation by N-methyltransferase from rabbit lung. The methylation of other amines (amphetamine and benzylamine) was similarly increased by decreases in pKa. The results suggest that the neutral nonprotonated amine is the molecular species attacked or preferred by this enzyme.

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.