Dopamine-p-hydroxylase inhibitors

Biosynthetic pathway inhibitors. In both the central and periphery nervous systems, the biosynthetic pathways for catecholamines, including the sympathetic nervous system transmitter noradrenaline, involve a number of enzymic conversions that may, in principle, be inhibited. There are several inhibitors known that interfere with catecholamine production (e.g, carbidopa or benzerazide) and may therefore act as antisympathetic agents. See dopa decarboxylase inhibitors dopamine P-hydroxylase inhibitors. 

REDUCTASE INHIBITORS DOPA-DECARBOXYLASE INHIBITORS DOPAMINE P-HYDROXYLASE INHIBITORS ENDOPEPTIDASE INHIBITORS HMG-COA REDUCTASE INHIBITORS NEUTRAL ENDOPEPTIDASE INHIBITORS NITRIC OXIDE SYNTHASE INHIBITORS PHOSPHOLIPASE INHIBITORS 5a-REDUCTASE INHIBITORS REVERSE TRANSCRIPTASE INHIBITORS THROMBOXANE SYNTHASE... 

As the result of a screening program examining microbial fermentation products for pharmacological activity (other than antibiotic activity), fusaric acid (10) was isolated from Fusarium oxysporum following the discovery that extracts were potent inhibitors of dopamine p-hydroxylase, and thus interfered with the biosynthesis in vivo of the pressor neurohormone, norepinephrine. To refine this lead, amidation of 10 via the acid chloride was carried out... 

An enzyme inhibitor of microbial origin with a simple structure, fusaric acid (XXXIV), is a hypotensive agent. This compound has been tested clinically as the free acid (29) and as the calcium salt (30) and is orally effective in man with a low incidence of side-effects. Dopamine-p-hydroxylase inhibitory action of this compound has been demonstrated in man (29). 

Agents that can inhibit dopamine-P-hydroxylase include disulfiram, fusaric acid, phenylpropargylamine, FLA 63, FLA 57, LY 10853 and SKF 102698. These agents are of value in experimental investigations, but none Is used clinically for this purpose (though disulfiram is used to modify ethanol metabolism by a different mechanism see aldehyde DEHYDROGENASE INHIBITORS). 

Many quinoline derivatives are important biologically active agents. 8-Hydroxyquinoline and some of its halogenated derivatives are used as antiseptics. Chloroquine 111 is one of the older but still important antimalarials. A -Alkyl-4-quinolone-3-carboxylic acid and systems derived therefrom are constituents of antibacterials (gyrase inhibitors [112]) such as nalidixic acid 112, ciprofloxazin 113 and moxifloxazin 114. The quinoline-8-carboxylic acid derivative 115 (quinmerac) is employed as a herbicide for Galium aparine and other broad-leaved weeds. Methoxatin 116, known as coenzyme PQQ is a heterotricyclic mammalian cofactor for lysyl oxidase and dopamine P-hydroxylase [113]. 

The next enzyme in the biosynthetic pathway to norepinephrine and epinephrine, dopamine p-hydroxylase. has been the subject of extensive research into its chemical mechanism and the subject of many enzyme inhibition studies. The inhibitors known to date, however, are primarily of basic biochemical research interest and have no therapeutic relevance. The same is true of phenylethanolamine-N-methyltransferase. the last enzyme in the biosynthesis of epinephrine in the adrenal medulla. 

Excess NE normally subjects tyrosine uptake to feedback inhibition. Tyrosine conversion to dopamine can be inhibited by methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. 

Metirosine (a-methyl-p-t5n osine) is a competitive inhibitor of the eruyme tyrosine hydroxylase, which converts t5U-osine to dopa as dopa is further converted to noradrenaline and adrenaline they are similarly depleted by metirosine. It is used as an adjuvant (with phenoxybenzamine) to treat phaeo-chromocytomas that caimot be removed surgically. Catecholamine synthesis is reduced by up to 80% over 3 days. It also readily penetrates the CNS and depletes brain noradrenaline and dopamine causing reserpine-like side effects (see above). Hence, in patients whose life expectancy is threatened more by tumour invasion than by mild or moderate hypertension, the need for the drug should be weighed carefully. 

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