4, 4, 6-Trimethyl-3, 4-dihydropyrimidine-2-thiol, an effective inhibitor of dopamine-β-hydroxylation in vivo

Abstract 4, 4, 6-Trimethyl-3, 4-dihydropyrimidine-2-thiol, although considerably less potent (1/500) than disulfiram as an inhibitor of dopamine-β-hydroxylation in vitro , is 10–20 times as potent as disulfiram, both administered intraperitoneally, in vivo . The pyrimidinethiol decreases the concentration of norepinephrine in the brain (mice and rats) but does not decrease the concentration of dopamine in that organ; it inhibits the depleting action of methyldopa and α- methyl -m- tyrosine on brain and heart norepinephrine, and of α- methyl -m- tyramine and α-methyl-dopamine on heart norepinephrine, and its effects upon tissue catecholamines are additive to those of DOPA and of a monoamine oxidase inhibitor; it inhibits restoration of the tyramine-pressor response in reserpine-treated rats by α-methyldopamine. The pyrimidinethiol is perhaps twice as potent as disulfiram as an inhibitor of alcohol metabolism in the rat, and in this function it, like disulfiram, acts at the aldehyde dehydrogenase step of oxidation. The pyrimidinethiol, like other thiourea derivatives, blocks the uptake of iodine by the rat thyroid gland in vivo . In this function it is about 1/150 as potent as propylthiouracil and six times as potent as disulfiram. The pyrimidinethiol is well absorbed after oral administration; for this reason, and because of its potency advantage over disulfiram, the compound should be superior to dilsulfiram in a number of situations.