EFFECT OF ALPHA-METHYL-5-HYDROXYTRYPTOPHAN ETHYL ESTER UPON TISSUE NOREPINEPHRINE LEVELS IN RATS AND MICE

α-Methyl-5-hydroxytryptophan (α-Me-5-HTP) has been shown to inhibit tyrosine hydroxylase in vivo, resulting in a decrease of tissue norepinephrine (NE) levels. Previously unreported studies had demonstrated that the compound was poorly absorbed after oral administration. The ethyl ester of α-Me-5-HTP is an orally active form, as indicated by blood levels of the compound and confirmed by its NE-depleting effect in mouse brain and rat brain, myocardium and adrenals. With single or multiple oral dosing schedules, which deplete rat myocardial NE to as low as 10 per cent of control, brain NE was lowered by 50 per cent. After these chronic dosing procedures, rat brain stem tyrosine hydroxylase was reduced only 20 per cent. Dose (50-400 mg/kg) and time (88-144 hr) studies with single oral doses showed that myocardial NE was markedly depleted at 24 hr by 50 mg/kg and that these NE levels were still below control level 144 hr after 400 mg/kg. The time study in rat brain and myocardium is compared with that produced by α-methyl tyrosine methyl ester, 400 mg/kg, p.o. Depletion in myocardium and the adrenal is marked by an initial rapid decline which exceeds that expected to occur after a total blockade of biosynthesis through inhibition of tyrosine hydroxylation. Other possible actions of the compound are discussed. © 1969.