Levodopa synthesis

The third method of levodopa synthesis consists of the acetylation of tyrosine using acetylchlo-ride in the presence of aluminum chloride and the subsequent oxidative deacylation of the formed 3-acetyltyrosine (10.1.2) using hydrogen peroxide in sodium hydroxide solution [4-7]. 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

Nonorganic and organometallic catalysts are also used to channel the reactions toward the chiral synthesis pathway. The drug called levodopa, (5)-3,4-dihydroxyalanine, is an effective drug against Parkinson s disease. It is stereoselectively manufactured using catalysts such as rhodium or ruthenium complexes. 

Methods of synthesis of levodopa from vanillin [8-14] have been suggested. According to one of them, condensation of vanillin with hydantoin and the subsequent reduction of the double bond in the formed product (10.1.4), after hydrolysis, gives racemic DOPA from which levodopa is isolated [8]. 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

Dopamine is the immediate precursor in the synthesis of norepinephrine (see Figure 6-5). Its cardiovascular effects were described above. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. It is an important neurotransmitter in the central nervous system and is involved in the reward stimulus relevant to addiction. Its deficiency in the basal ganglia leads to Parkinson s disease, which is treated with its precursor levodopa. Dopamine receptors are also targets for antipsychotic drugs. 

Enantioselective synthesis is particularly important in the pharmaceutical industry, because only one enantiomer of a chiral drug is likely to have the desired effect. For example, levodopa [(- )-dopa or Z-dopa] is used in patients with Parkinson s disease to counteract a deficiency of dopamine, one of the neurotransmitters in the brain. Dopamine... 

Furthermore, both methyldopa and reserpine, that essentially interfere with the catecholamine synthesis as well as its storage, exacerbate the Parkinson syndrome and, therefore, antagonize the activity of levodopa. The pharmacological profile of levodopa actually synergized by antimuscarinics. 

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