First Generation Catecholomethyltransferase Inhibitors

During the 1960s and 1970s, a number of COMT inhibitors were identified and studied. Pyrogallol (1,2,3-trihydroxybenzene) was the first COMT inhibitor to be identified (26,27), but its short duration of action, toxicity (methemoglobinemia and renal impairment), and probable lack of COMT specificity precluded its clinical use (11). The list of additional COMT inhibitors that were studied and subsequently abandoned as potential therapeutic agents is quite long. Catechol itself, adnamine and noradnamine, various flavonoids, tropolone and its derivatives, 8-hydroxyquinolines, S-adenosylhomocysteine, sulfhydryl-binding agents, pyrones and pyridones, papaveroline, methylspinazarin, 2-hydroxylated estrogens, and 3-mercaptotyramine represent only a partial listing of such compounds (11). Even the two agents that are primarily recognized as inhibitors of AAAD, carbidopa and benserazide, have some modest COMT-inhibiting properties, although not enough to be clinically relevant (11).

Several of these early COMT inhibitors did undergo pilot testing in humans. N-butyl gallate (GPA 1714), a derivative of gallic acid, was found to be effective in alleviating signs and symptoms of PD when administered to 10 patients (28). The dose of levodopa was reduced by an average of 29% and the drug was also noted to alleviate nausea and vomiting. No significant adverse effects were noted in this initial study, but testing was eventually abandoned because of its toxicity (29). Another compound, 3,4-dihydroxy-2-methylpropiophenone (U-0521), demonstrated significant COMT inhibition in animal studies, but when it was administered orally to a single human in progressively increasing doses, it demonstrated no effect on ery-throcyte COMT activity (29).

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