DOPA decarboxylase inhibition

Catechol O-methyltransferase inhibition represents therefore a valuable adjuvant to the L-DOPA decarboxylase inhibition. Unfortunately, tolcapone exhibited... 

Catechol 0-methyltransferase inhibition represents therefore a valuable adjuvant to the 1-DOPA decarboxylase inhibition. Unfortunately, toicapone exhibited severe liver damages and had to be removed from the market. The corresponding vinyiogue entacapone is devoided of these side effects. ... 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

Persson, S.-A. (1977) The effect of LSD and 2-bromo LSD on the striatal DOPA accumulation after decarboxylase inhibition in rats. Eur. J. Pharmacol., 43 73-83. 

The first syntheses of a-allenic a-amino acids [131,133] took advantage of Steg-lich s [134] protocol for the oxazole-Claisen rearrangement of unsaturated N-ben-zoylamino acid esters (Scheme 18.46). Thus, treatment of the propargylic ester 143 with triphenylphosphine and tetrachlormethane furnished the allenic oxazolone 144, which was converted into the amino acid derivative 145 by methanolysis. Stepwise deprotection finally led to the allenic DOPA analog 146, which shows a much higher decarboxylase-inhibiting activity than a-vinyl- and a-ethynyl-DOPA [133],... 

Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of... 

Fig. 3. Schematic representation of the neurochemical events associated with neurotransmitter synthesis, release, re-uptake and metabolism in axons of diencephalic DA neurons terminating in classical synapses (Top Panel), and TIDA neurosecretory neurons terminating in close proximity to the hypophysial portal system (Botton Panel). Arrows with dashed lines represent end-product inhibition of TH activiy by DA (Top + Bottom Panels) or DA presynaptic autoreceptor-mediated inhibition of DA synthesis and release (Top Panel). Abbreviations COMT, Catechol-O-methyltransferase D, dopamine DDC, DOPA decarboxylase DOPA, 3,4-dihydrophenylalanine DOPAC, 3,4-dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine TH, tyrosine hydroxylase.

LEVODOPA, SELEGILINE, POSSIBLY RASAGILINE, ENTACAPONE, TOLCAPONE MAOIs Risk of adrenergic syndrome -hypertension, hyperthermia, arrhythmias - and dopaminergic effects with selegiline Levodopa and related drugs are precursors of dopamine. Levodopa is predominantly metabolized to dopamine, and a smaller proportion is converted to epinephrine and norepinephrine. Effects are due to inhibition of MAOI, which breaks down dopamine and sympathomimetics Avoid concurrent use. Onset may be 6-24 hours after ingestion. Carbidopa and benserazide, which inhibit dopa decarboxylase that converts L-dopa to dopamine, is considered to minimize this interaction. However, MAOIs should not be used in patients with Parkinson s disease on treatment with levodopa. Imipramine and amitriptyline are considered safer by some clinicians... 

LEVODOPA VITAMIN B6 1 efficacy of levodopa (in the absence of a dopa decarboxylase inhibitor) A derivative of vitamin B6 is a cofactor in the peripheral conversion of levodopa to dopamine, which 1 the amount available for conversion in the CNS. Dopa decarboxylase inhibitors inhibit this peripheral reaction Avoid co-administration of levodopa with vitamin B6 co-administration of vitamin B6 with co-beneldopa or co-careldopa is acceptable... 

Another dmg closely similar to DOPA but used for different applications is a-methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the false transmitter a-methyl-dopamine. Like dopamine or norepinephrine, a-methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic a,-receptors, it does activate 0C2-receptors. It will therefore inhibit the further release of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accomplishes the same in a less roundabout manner). 

Carbidopa is commonly added to L-DOPA in the treatment of Parkinson s disease. Carbidopa inhibits dopa decarboxylase (the enzyme active at this step in the formation of dopamine), but does not cross the blood brain barrier. Thus, the administered L-DOPA is free to act in the brain but is inhibited from acting in the periphery where it may have unwanted side effects, like nausea and vomiting. 

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. 

DOPA to dopamine, by the cytosolic enzyme, DOPA decarboxylase. In the central and peripheral nervous systems, dopamine is converted to noradrenaline by dopamine-P-hydroxylase (DBH), which, though a relatively non-specific enzyme, is restricted to catecholamine-synthesizing cells. It can be inhibited by many drugs, which brings the risk of complex drug interactions. In the peripheral sympathetic nervous system, noradrenaline, in turn, is converted to adrenaline, by phenylethylamine N-methyl transferase, so inhibition of DBH can therefore, in principle, slow production of both adrenaline and noradrenaline but normally tyrosine hydroxylase is the rate-limiting step in the synthetic pathway. 

---