Tyrosine hydroxylase and dopamine β-hydroxylase inhibiting properties of a new series of pyridazinyl hydrazones

Abstract

New pyridazinyl hydrazones are described as a novel class of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) inhibitors. A great number of these substances showed potent TH- or DBH-inhibiting capacities. The structure-activity analysis suggested an important role for the N 2 substitution of hydrazine in the inhibiting characteristics of the compounds. β-Substituted pyridazinyl hydrazones showed favourable TH- or DBH-inhibiting activities, whereas the free hydrazines were only slightly effective on tyrosine hydroxylation and noneffective on dopamine hydroxylation. The β-ketoester derivatives of 6-chloro-3-pyridazinyl hydrazones were characterized as potent DBH-inhibiting substances while the cyclohexylidene or the bicycloheptylidenepyridazinyl hydrazones were found to be marked TH- and DBH-blocking agents. Among the above substances, GYKI 11679 {chemically 1-(6-morpholino-3-pyridazinyl)-2-[(1-tertiary-butoxycarbonyl)-2-propylidene] hydrazine} has been found to be the most potent inhibitor of tyrosine hydroxylation both in vitro and in vivo. Its in vitro as well as its in vivo TH-blocking activity was comparable with that of α-methyltyrosine. The most effective representative of this new series on dopamine and tyramine hydroxylations in vitro and in vivo, compound GYKI 11473 {chemically 1-(6-chloro-3-pyridazinyl)-2-[(1-ethoxycarbonyl)-2-propylidene] hydrazine}, has been characterised as a reversible and competitive inhibitor of DBH with dopamine and a noncompetitive inhibitor of DBH with tyramine as substrate at concns of 10 −5–10 −6 M. The compound has also been found to inhibit the neuronal and the vesicular uptake of dopamine in hypothalamic slices. GYKI 11473 showed a greater effect in the heart than in the brain and its in vivo efficiency has been established as being more potent than those of fusaric acid in both tissues. The noradrenaline (NA) determinations suggested similar, but not equal, and exclusive contributions of TH and DBH in the maintenance of NA pools in these tissues.