Inhibitors Of Phenylethanolamine N-methyltransferase Research Articles

The effect of SK&F 64139, an inhibitor of phenylethanolamine- N-methyl transferase (PNMT), on adrenaline and noradrenaline content in sympathetic neurons of the cod, Gadus morhua

1. The effect of SK&F 64139, a selective PNMT inhibitor, on PNMT activity and catecholamine levels in sympathetic neurons of the atlantic cod, Gadus morhua, has been studied. 2. The drug was found to be a potent competitive inhibitor of cod PNMT in vitro. Intramuscular injections of SK&F 64139 (30 mg/kg per day) caused a decrease of spleen adrenaline content after 6 and 9 days of administration, coupled with an increased noradrenaline level. 3. The effect of SK&F 64139 and increased nervous activity on the catecholamine levels was studied in the perfused spleen. Increased splanchnic nerve activity alone caused a marked increase in spleen noradrenaline levels while the adrenaline content was uncharged. The presence of SK&F 64139, in a concentration known to produce a 75% PNMT inhibition in vitro, caused only minor further effects of spleen catecholamine content during these experimental conditions. 4. It is concluded that adrenaline is synthesized from noradrenaline in the cod sympathetic nerve terminals. The results indicate a low turnover of adrenaline in these terminals and the presence of a short-term neurogenic control of catecholamine synthesis is suggested.

Studies with a PNMT inhibitor

DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N-methyltransferase (PNMT). In animal studies, a plasma level of 0.35 microgram/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single-dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 microgram/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.

Effect of phenylethanolamine N-methyltransferase and dopamine-β-hydroxylase inhibition on epinephrine levels in the brain

The effects of phenylethanolamine N-methyltransferase (PNMT) and dopamine-β-hydroxylase (DβH) inhibition on the epinephrine content in specific regions of the brain were studied. SKF 64139, a potent PNMT inhibitor, is effective in lowering brain epinephrine levels. The time course of PNMT inhibition by SKF 64139 parallels the lowering of epinephrine levels in the brain. Diethyldithiocarbamate (DDC), a potent inhibitor of DβH, is effective in lowering norepinephrine and epinephrine levels and in elevating dopamine levels in the analyzed regions of the brain. The epinephrine levels in the brain appear to be under similar biosynthetic control as in the adrenal glands.

The effects of an inhibitor of phenylethanolamine N-methyltransferase upon stimulated adrenal catecholamine release and excretion in the rat.

SK&F 64139, an inhibitor of adrenal phenylethanolamine N-methyltransferase (PNMT), was found to significantly decrease 2-deoxy-D-glucose (2-DG) induced epinephrine excretion in the conscious rat under conditions where the former agent was administered chromically at 50 and 200 mg/kg/day over a 12-day period and 2-DG was administered after 3, 7 and 11 days of treatment. The reduced epinephrine output caused by SK&F 64139 in response to 2-DG was accompanied by an increased norepinephrine excretion pattern at 200 mg/kg/day of the compound. The reductions in epinephrine excretion were also associated with significant decreases in adrenal epinephrine and increases in the norepinephrine content.

The long term effects of an inhibitor of phenylethanolamine N-methyltransferase upon adrenal epinephrine biosynthesis.

Chronic administration of SK&F 64139, an inhibitor of phenylethanolamine N-methyltransferase (PNMT), initially resulted in a lowered adrenal epinephrine content in both the rat and squirrel monkey adrenal gland. With continued dosing, however, these levels returned toward control. The latter changes were accompanied by increased adrenal levels of norepinephrine and PNMT, but not by decreased plasma drug levels. These results suggest that long-term pharmacological PNMT inhibition may evoke compensatory mechanisms to maintain adrenal epinephrine biosynthesis under basal laboratory conditions.

Adrenaline-forming enzyme in brainstem: elevation in genetic and experimental hypertension.

The adrenaline-forming enzyme (phenylethanolamine N-methyltransferase) was elevated in the A1 and A2 regions of the brainstem of 4-week-old spontaneously (genetic) hypertensive rats and in the A1 region of adult experimentally (deoxycorticosterone acetate and sodium chloride) hypertensive rats. The administration of a phenylethanolamine N-methyltransferase inhibitor to experimentally hypertensive animals caused a reduction of the elevated blood pressure to normal values. These results implicate adrenaline-containing neurons in the brainstem in the development of hypertension.

Regulation of phenylethanolamine N-methyl transferase

Phenylethanolamine N-methyl transferase (PNMT) catalyzes the methylation of norepinephrine, forming epinephrine in the adrenal medulla. In vitro, PNMT accepts a variety of phenylethanolamines and phenylethylenediamines as substrates. It is inhibited by phenethylamines and other compounds structurally similar to its substrates, as well as by agents that bind to sulfhydryl groups. Specific inhibitors of PNMT may be useful pharmacologic tools and potentially drugs. A group of benzylamines, including 2,3-dichloro-α-methylbenzylamine, are among the most potent inhibitors presently known. In vivo, maintenance of PNMT levels in the adrenal medulla is dependent upon an adequate supply of glucocorticoids from the adrenal cortex. Neural input to the medulla may also influence the enzyme level. The possibility that product inhibition may influence PNMT activity in vivo requires further study.

Inhibition of phenylethanolamine N-methyltransferase by benzylamines. 1. Structure-activity relationships.

Inhibition of phenylethanolamine N-methyltransferase by benzylamines. 1. Structure-activity relationships.

Inhibition of phenylethanolamine N-methyltransferase by benzylamines. 2. In vitro and in vivo studies with 2,3-dichloro- -methylbenzylamine.

Inhibition of phenylethanolamine N-methyltransferase by benzylamines. 2. In vitro and in vivo studies with 2,3-dichloro- -methylbenzylamine.