New inhibitors of dopamine β-hydroxylase

Abstract

A32390A, 1,6-di-O-(2-isocyano-3-methylcrotonyl)- d-mannitol, obtained from fermentation broths of a species of Pyrenochaeta, inhibited DBH in vitro and lowered heart norepinephrine levels in vivo in rats. A32390A had less effect on adrenal catecholamine levels and did not lower brain norepinephrine levels. Associated with the inhibition of norepinephrine synthesis in vivo was a reduction of blood pressure by A32390A in DOCA hypertensive rats. Although A32390A was effective when given by either intraperitoneal or subcutaneous injection, it did not lower norepinephrine levels or blood pressure when given orally. CHMI (1-cyclohexyl-2-mercapto-imidazole) was the most active among several methimazole derivatives studied as a DBH inhibitor that reduced norepinephrine levels preferentially in brain. The initial decline in brain norepinephrine levels following CHMI injection could be used as an index of norepinephrine turnover. Lowering of brain norepinephrine levels by CHMI on the second day of proestrus in female rats prevented the surge of plasma LH levels that normally occurred on the afternoon of proestrus.