L-methyldopa

Lippold BC and Jaeger I, Stability and dissociation constants of L-dopa and alpha-L-methyldopa, Arch. Pharm. Weinheim., 306, 106-117 (1973). 

Separations in this field with different eluent systems have been published independently (Fig. 12, Refs. 174,175,200). As can be seen from Table 11, D,L-methyldopa can also be separated without problems (199). 

L-methyldopa The molecularly imprinted polymeric microspheres (MIPMs) for L-methyldopa (LMD) were synthesized by precipitation polymerization. The influences of synthetic conditions such as polymerization temperature, the amount of initiator (2,2 -Azobis(isobutyronitrile)) and the property of template on the morphologies and diameter sizes of MIPMs were investigated in details. for controlled release of L-methyldopa [236]... 

Pharmaceutical Products. Rhc ne-Poulenc offers a flaked technical-grade vanillin, Vaniltek, to be used in pharmaceutical appHcations. The single largest use for vanillin is as a starting material for the manufacture of an antihypertensive dmg having the chemical name of Methyldopa or L-3-(3,4-dihydroxyphenyl)-2-methylalanine. 

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... 

C4H5N3O2 932-52-5) see Uramustine L-a-amino-a-vanillylpropionamide (C11H15N2O3 6555-09-5) sec Methyldopa DL-a-amino-a-vanillylpropionitrile (C11H14N2O2 6555-27-7) see Methyldopa L-a-amino-a-vanillylpropionitrile (C H]4N202 14818-96-3) see Methyldopa amitriptyline... 

C20H25NO4) see Moxaverine L-3-(3,4-dimethoxyphenyl)-2-metbylalanine (C12H17NO4 39948-18-0) see Carbidopa ( )-3-(3,4-dimethoxyphenyl)-2-methylalanine (C 2H,7N04 10128-06-0) see Methyldopa 2-(3,4-dimethoxyphenyI)-3-methylbutyronitrile (CjjH 17NO2 20850-49-1) see Verapamil... 

This soluble enzyme requires pyridoxal phosphate for the conversion of L-dopa to 3,4-dihydroxyphenylethyl-amine (dopamine). Compounds that resemble L-dopa, such as a-methyldopa, are competitive inhibitors of this reaction. a-Methyldopa is effective in treating some kinds of hypertension. 

Figure 9 Plasma profile of L-a-methyldopa following intravenous dose of L-a-methyl-dopa and jejunal dose of L-a-methyldopa-phenylalanine and L-a-methyldopa (n = 6-7). ( ) L-a-methyldopa following jejunal dose of prodrug (V) L-a-methyldopa jejunal dose ( ) L-a-methyldopa intravenous dose.

V. Amino acid or peptidyl L-a-Methyldopa cynamide, e.g., A-carbobenzoxyglycyl Dipeptidyl derivative, e.g., a-methyldopaphenylalanine 46-48... 

Hu Ming, HI Mosberg, GL Amidon. Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methyldopa Carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-alpha-methyldopa. Pharm Res 6(1) 66—69, 1989. 

M Asgharnejad, GL Amidon. Improved oral delivery via the peptide transporter A dipeptide prodmg of L-alpha-methyldopa. Pharm Res 9 S-248, 1992. 

Hu, M. and R. Borchardt. Mechanism of L-alpha-methyldopa transport through a monolayer of polarized human intestinal epithelial cells (Caco-2)., Pharm. Res. 1990, 7, 1313-1319... 

L-leucine and L-phenylalanine in human jejunum in vivo. P r were measured using a single-pass perfusion technique at concentrations of 2.5 mM, 6.7 mM, 40 mM and 0.06 mM for l-dopa, a-methyldopa, L-leucine and L-phenylalanine, respectively. 

Hu, M., SuBEAMANIAN, P., MOSBERG, H. I., Amidon, G. L., Use of dipeptide carrier system to improve the intestinal absorption of L-a-methyldopa carrier kinetics, intestinal permeabilities and in vitro hydrolysis of dipep-tidyl derivatives of L-a-methyldopa, Pharm. Res. 1989, 6, 66-70. 

A series of peptide prodrugs ofh-a-methyldopa were prepared and shown to exhibit high affinity for the peptide carrier system [32], In an in situ intestinal perfusion model, the prodrugs Phe-L-a-methyldopa (6.10) and l-a-methyldopa-Phe (6.11) showed permeabilities that were 10- and 20-times higher, respectively, than that of L-a-methyldopa. The other derivatives examined (Gly- and Pro-L-a-methyldopa, L-a-methyldopa-Pro) also had better permeabilities. These and other results indicate that the peptide transport system has a relatively low substrate specificity and can indeed be targeted by peptide prodrugs to improve absorption [33],... 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored however, unlike the endogenous mediator, it has a higher affinity for a2- than for ai-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral adrenergic neurons. 

Uses. The main application of vanillin is the flavoring of foods (e.g., ice cream, chocolate, bakery products, and confectioneries). Small quantities are used in perfumery to round and fix sweet, balsamic fragrances. Vanillin is also used as a brightener in galvanotechnical processes and is an important intermediate in, for example, the production of pharmaceuticals such as L-3,4-dihydroxyphenylalanine (l-DOPA) and methyldopa. 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

Pharmacologic strategies for dopaminergic therapy of Parkinson s disease. Drugs and their effects are highlighted (see text). MAO, monoamine oxidase COMT, catechol-O-methyltransferase DOPAC, dihydroxyphenylacetic acid L-DOPA, levodopa 3-OMD, 3-0-methyldopa. 

As a result of a high index of clinical suspicion and, on occasion, supporting biochemical data from other investigations, one of the first specialist investigations to ascertain whether a patient has an inborn error of biogenic amine metabolism is, as mentioned above, analysis of the CSF concentrations of HVA and 5HIAA. This is often performed in conjunction with the measurement of 3-methyldopa (3-MD), also known as 3-methoxytyrosine. 3-MD is formed from L-dopa via COMT activity and accumulates in conditions where aromatic amino acid decarboxylase activity is impaired. The chemical structures of HVA, 5HIAA and 3-MD are shown in Fig. 6.2.1. 

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