126.96.36.199 Peripheral aromatic amino acid decarboxylase (AADC) inhibitors
Noradrenaline is synthesized at the nerve endings of the postganglionic fibre by a series of reactions from tyrosine (see Equation [8.44]). Inhibitors of AADC have been synthesized as potential antihypertensive drugs on the basis that a decrease in the biosynthesis of noradrenaline would deplete noradrenaline stores at the nerve endings and lead to a decrease in blood pressure. Although many reversible inhibitors of the enzyme are known from in vitro studies (e.g. methyldopa (8.123)) only a few exert an antihypertensive action in vivo and probably by an alternative mechanism since inhibition of the first step in the pathway is not involved (see Section 8.2.1). However, this work led to the discovery of the inhibitors carbidopa (8.124) and serazide (8.125) which have proved useful as adjuvants in the treatment of Parkinson's disease with L-dopa. L-Dopa penetrates into the basal ganglia of the brain where it is decarboxylated to the active agent, dopamine. Large doses of L-dopa are required in therapy since it is depleted in the plasma by peripheral AADC to dopamine which is readily removed by monoamine oxidase. Combination of L-dopa with serazide or carbidopa leads to decreased metabolism of L-dopa so that smaller effective
doses can be used in therapy which have fewer side-effects than large doses. Necessary features of these inhibitors are that they do not penetrate the blood-brain and interfere with the decarboxylation of L-dopa to dopamine in the brain and, for the reason given above, neither do they reduce the synthesis of endogenous amines in the peripheral tissues.
AADC is a pyridoxal phosphate-dependent enzyme and serazide and carbidopa are potent pseudo-irreversible inhibitors of the enzyme. They probably function by binding to pyridoxal phosphate as carbonyl group reagents.
Several mechanism-based inactivators of AADC have been described and the a-monofluoromethyl (8.126) and a-difluoromethyl (8.127) derivative of dopa deserve special mention here. These compounds are time-dependent irreversible inhibitors of the enzyme. During one turnover of the inhibitor by the enzyme, one equivalent each of CO2 and F- is released and the inhibitor binds in a 1:1 ratio to the enzyme-cofactor complex. It is not clear whether the reaction pathway occurs through the mechanism shown in Equation [8.41] or in Equation [8.42]. a-Difluoromethyldopa is comparable to carbidopa and effectively protects exogenous dopa against decarboxylation. It inhibits brain AADC only at high concentrations. a-Monofluoromethyldopa effectively inhibits AADC centrally as well as peripherally and the resulting depletion of peripheral catecholamines produces antihypertensive effects which can be reversed by i.v. infusions of dopamine.
188.8.131.52 Ornithine decarboxylase (ODC) inhibitors
Naturally occurring polyamines such as putrescine, spermidine and spermine are required for cellular growth and differentiation. Spermidine and spermine are derived in human-type cells from putrescine. Putrescine is synthesized by decarboxylation of ornithine, catalysed by the pyridoxal phosphate-dependent enzyme ornithine decarboxylase (ODC) (Equation [8.45]). ODC has a very short biological half-life and its synthesis is stimulated 'on demand' by trophic agents and controlled by putrescine and spermidine levels. ODC has been considered a suitable target enzyme for the control of growth in tumours and disease caused by parasitic protozoa.
a-Difluoromethylornithine (eflornithine; (8.128)) is a mechanism-based inactivator of the enzyme and irreversibly inhibits the enzyme by the general mechanism previously depicted with elimination of a single fluoride ion to produce a conjugated electrophilic imine (c.f. 8.120) which reacts with the nucleophilic thiol of Cys-390. A further fluoride ion is then eliminated which, following transaldimation with Lys-69, leads to the species Cys-390-S-CH=C(NH2)-(CH2)3-NH2 which loses ammonia and cyclises to (2-(1-pyrroline)methyl) cysteine.
Eflornithine has low toxicity in animals and has shown antineoplastic and antiprotozoal actions in clinical trials. £-2-(fluoromethyl) dehydroornithine (8.129), is another derivative which is a mechanism-based inactivator of the enzyme. The methyl or ethyl esters are effectively hydrolysed at the higher cellular concentrations attained due to improved absorption and are 10 time more effective than eflornithine or (8.129) in decreasing ODC activity in animal tissues, an effect which is long lasting. The methyl ester is also more active than eflornithine against trypanosomiasis and malaria in mice.
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