L-a-Methyldopa

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... 

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

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],... 

L-a-methyldopa a substrate for the amino acid transporter. In Caco-2 cells, the active transport of this dmg by the amino acid transporter was seven times higher than transport by passive diffusion. Its absorption may be further increased by upregulating the amino acid transporter, as has been observed in the 20-70% stimulation of carrier-mediated amino acid transport by treatment of 0.2 mg/kg growth hormone. 

Harrison, W. H., Gray, R. M., and Solomon, L. M., Incorporation of L-DOPA, L-a-methylDOPA and DL-isoproterenol into guinea pig hair, Acta Dermatovener (Stockholm), 54, 249,1974. 

Synonym. (— )-L-a-Methyldopa Hydrazine Proprietary Name. It is an ingredient of Sinemet. 5-2-(3,4-Dihydroxybenzyl)-2-hydrazinopropionic acid monohydrate... 

Figure 6 Plasma profile of L-a-methyldopa following intravenous dose of L-a-methyldopa and jejunal dose of L-a-methyldopa and L-a-methyldopa-phenylalanine... 

The end product yielded by this process is DL-a-methyldopa, a racemate. The antihypertensive effect, however, is exerted solely by the L-(-)-isomer. The isomers can be separated with the aid of 1-phenethylamine at the stage of dl-3-(3, 4 -dimethoxyphenyl)-2-methylalanine, or with the aid of quinine at the stage of DL-a-methyldopa [255]. Both procedures are too expensive for large-scale production. The industrial process used today is fractionated crystallisation [276]. For this purpose, DL-a-methyldopa is dissolved in water in the form of the bisulfite salt and the l-(—)-isomer is crystallised from the supersaturated solution by inoculation with pure L-(—)-a-methyldopa. 

Tyrosine hydroxylase shows a marked preference for L-Tyr as a substrate D-Tyr, L-tiyptophan, DL- i-Tyr and 3-iodo-Tyr are inactive as substrates. The enzyme will, however, catalyse a slow conversion of L-phenylalanine to L-Tyr, and L-fls-methyl-p-Tyr to L-a-methylDOPA. 

But also in many other fields unnatural amino acids are used, e.g., for the antihypertensive drugs Aldomet (L-a-methylDOPA) (5) [4], the ACE inhibitors enalapiil and lisinopiil (structures not shown) [5], and the recently developed HTV-protease inhibitors... 

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