Dihydroxyphenylalanine inhibitors

L-Dihydroxyphenylalanine 4-Dihydroxyphenylethylamine Dimeric Transcription Factors Dioxins Dipeptidase Dipeptidylpeptidase Dipeptidylpeptidase IV Direct Thrombin Inhibitors Discharge of Neurons... 

Mechanism of Action A tyrosine hydroxylase inhibitor that blocks conversion of tyrosine to dihydroxyphenylalanine, the rate limiting step in the biosynthetic pathway of catecholamines. Therapeutic Effect Reduces levels of endogenous catecholamines. 

Tornwall M, Mannisto PT. Effects of three types of catechol-(9-methylation inhibitors on 1-3,4-dihydroxyphenylalanine-induced circling behaviour in rats. European Journal of Pharmacology 1993 250 77-84. 

Tyrosinase inhibitors prevent browning in foodbecause they inhibit the oxidation caused by the enzyme tyrosinase. Cuminaldehyde is identified as a potent mushroom tyrosinase monophenol monooxygenase inhibitor from cumin seeds, ft inhibits the oxidation of L-3,4-dihydroxyphenylalanine (l-DOPA) by mushroom tyrosinase with an ID50 of 7.7g/ml (0.05 mM). Its oxidized analogue, cumic acid (p-isopropylbenzoic acid), also inhibits this oxidation with an 1D50 of 43g/ml (0.26mM). These two inhibitors affect mushroom tyrosinase activity in different ways (Kubo and Kinst-Hori, 1998). 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxyphenylalanine (levo-dopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by dopa decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed and is likely to cause undesirable effects (vomiting hypotension p.116). Extracerebral production of dopamine can be prevented by inhibitors of dopa decarboxylase (carbidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. 

Carboni E, Tanda G, Di Chiara G (1992) Extracellular striatal concentrations of endogenous 3,4-dihydroxyphenylalanine in the absence of a decarboxylase inhibitor—A dynamic index of dopamine synthesis in vivo. / Neurochem 59 2230-2236. 

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

Unfortunately, our knowledge of the mode of action of these substances is so limited that it is difficult to decide what chemical approaches would prove beneficial. In controlled studies with depressed patients, the feeding of catechol amine precursors such as a-dihydroxyphenylalanine alone or with imipramine has not clinically altered the depressed state in patients who have failed to respond to imipramine or monamine oxidase inhibitors alone (12). These studies have raised further problems concerning the role of the catechol amines in depressed states. 

The product is applied for the treatment of Parkinsonism that is caused by a lack of l-dopamine and its receptors in the brain. L-Dopamine is synthesized in organisms by decarboxylation of L-3,4-dihydroxyphenylalanine (L-dopa). Since L-dopamine cannot pass the blood-brain barrier L-dopa is applied in combination with dopadecarbox-ylase-inhibitors to avoid formation of L-dopamine outside the brain. Ajinomoto produces L-dopa by this lyase-biotransformation with suspended whole cells in a fed batch reactor on a scale of 250 t a-1. Much earlier, Monsanto has successfully scaled up the chemical synthesis of L-dopa (Fig. 19-38). 

The second impetus in this field came from the elucidation of the metabolic pathways leading to the endogenous synthesis of norepinephrine (NE) and its ultimate oxidative degradation. The availability of specific enzyme inhibitors capable of blocking (a) the ra-hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA), (b) the decarboxylation of... 

DDC catalyzes the conversion of L-3,4-dihydroxyphenylalanine (l-DOPA) into dopamine (Figure 10), a neurotransmitter found in the nervous system and peripheral tissues of both vertebrates and invertebrates and also in plants where it is implicated in the biosynthesis of benzylisoquinoline alkaloids. " DDC also catalyzes the decarboxylation of tryptophan, phenylalanine, and tyrosine and of 5-hydroxy-L-tryptophan to give 5-hydroxytryptamine (serotonin), and, therefore, is also referred to as aromatic amino acid decarboxylase. Inhibitors of DDC, for example, carbiDOPA and benserazide, are currently used in the treatment of Parkinson s disease to increase the amount of l-DOPA in the brain. 

Acetylcholine, serotonin, norepinephrine, and tryptamine are noncompetitive inhibitors whereas epinephrine and dihydroxyphenylalanine are activators of GDH (360). Mitochondrial lipids have also been reported to be inhibitory, among them phosphatidylcholine, phosphatidylethanol-amine, cardiolipin, and phosphatidylserine (361). 

Kojic acid and arbutin are tyrosinase inhibitors. Kojic acid inhibits tyrosinase activity by chelation and as an antioxidant, while arbutin is a competitive inhibitor of tyrosinase. To impart hydrophobicity to these compounds to prevent degradation, phosphatidyl-kojic acid and phosphatidyl-arbutin were synthesized from dipalmitic-PC (DPPC) [43]. Their inhibition of l-DOPA (3,4-dihydroxyphenylalanine) to dop-achrome (precursor of melanin), catalyzed by tyrosinase in vitro, was of a similar level to the parent compounds. These phosphatidyl derivatives show promise for application in the cosmetics industry. 

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. 

After partial inhibition of MAO (with pargyline 4—24 h prior to the test), the response to 3,4-dihydroxyphenylalanine (DOPA), e.g. squeaking, jumping and fighting, is markedly enhanced by tricyclic antidepressants. MAO inhibitors, of course, produce the same response without pretreatment with pargyline. A survey of possible interference with other classes of drugs has not been published. 

A, adrenaline COMT, catechol-O-methyl transferase CSF, cerebrospinal fluid DA, 3,4-dihydroxyphenylethylamine (dopamine) Dopa, 3,4-dihydroxyphenylalanine 5HIAA, 5-hydroxyindoleacetic acid 5HT, 5-hydroxytryptamine (serotonin) 5HTP, 5-hydroxytryptophan HVA, 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid) MAO, monoamine oxidase MAOI, monoamine oxidase inhibitor MHPG,... 

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