Levodopa 3,4-dihydroxyphenylalanine

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). 

Because the underlying problem in Parkinson disease is a deficiency of dopamine in the basal ganglia, simple substitution of this chemical would seem to be a logical course of action. However, dopamine does not cross the blood-brain barrier. Administration of dopamine either orally or parenterally will therefore be ineffective because it will be unable to cross from the systemic circulation into the brain where it is needed. Fortunately, the immediate precursor to dopamine, dihydroxyphenylalanine (dopa Fig. 10-2), crosses the blood-brain barrier quite readily. Dopa, or more specifically levodopa (the L-isomer of dopa), is able to cross the brain capillary endothelium through... 

Dopamine is synthesized in the terminals of dopaminergic fibers originating with the amino acid tyrosine and, subsequently, L-dihydroxyphenylalanine (L-dopa or levodopa), the rate-limiting metabolic precursor of dopamine. Fortunately, L-dopa is significantly less polar than dopamine and can gain entry into the brain via an active process mediated by a carrier of aromatic amino acids. Although L-dopa is itself basically pharmacologically inert, therapeutic effects can be produced by its decarboxylation to dopamine within the CNS. 

Levodopa, (laevo-dihydroxyphenylalanine) is the principle drug in this group. Replacement therapy with dopamine itself is not possible because it does not pass the blood-brain barrier. Levodopa is the precursor of dopamine and it does penetrate the brain where it is converted in the neurons to dopamine by decarboxylation. 

The classic example of this approach involves the use of levodopa (l-3,4-dihydroxyphenylalanine, Figure 8.13) to treat Parkinson s disease [58]. Parkinson s disease is distinguished by the marked depletion of dopamine— an essential neurotransmitter—in the basal ganglia. Direct dopamine replacement is not possible, because dopamine does not permeate through the blood-brain barrier. However, the metabolic precursor of dopamine, levodopa, is transported across brain capillaries by the neutral amino acid transporter (see Table 5.5 and the related discussion). Peripheral administration of levodopa, therefore, produces an increase in levodopa concentration within the central nervous system some of these molecules are converted into dopamine due to the presence of decarboxylate enzymes in the brain tissue, but decar-boxylate activity is also present in the intestines and blood. To prevent conversion of levodopa into dopamine before entry to the brain, levodopa is usually administered with decarboxylase inhibitors. 

Dopamine replacanent - This most effective treatment for Parkinson s disease is supplied by the naturally-occurring amino acid levodopa (I, L-3, -dihydroxyphenylalanine " ). In the usual oral doses of 2.5 to 6 g daily it enters the brain and is deceurboxylated to form dopamine (II)... 

Dopamine. Like noradrenaline, this central neurotransmitter (3,4-dihydroxyphenylalanine) works by activating an adenylate cyclase. Human diseases are associated with both deficiency and excess. In Parkinson s disease, specific brain centres lack dopamine which is restored by treatment with levodopa. Major tranquillizers such as chloropromazine, work by blocking the dopamine receptor in the corpus striatum. Preliminary work has been done on isolation of the dopamine receptor. Meanwhile, receptor areas in the corpus striatum of the brain are monitored by their ability to bind H-haloperidol, which correlates well with the pharmacological effect of other psycholeptics (see Section 13.8) (Schwarcz et al. ... 

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