A-Methyldopa

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. 

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

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... 

The NHase and amidase from Rhodococcus rhodochrous IFO 15 564 was studied using a series of a,a-disubstituted malononitriles. This amidase preferentially hydrolyzes the pro (R) amide of the prochiral di-amide, which is an intermediate resulting from the nonenantiotopic NHase activity on the dinitrile substrate. This transformation was combined with a Hofmann rearrangement to generate a key precursor of (A)-methyldopa in 98.2% ee and 95% yield (Figure 8.5) [41],... 

Mechanism of L-a-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. 

As indicated earlier, a-methyldopa treatment of hypertension sometimes results in the appearance of parkinsonian symptoms. This is presumed to be a consequence of DA depletion by replacement of DA with the relatively inactive false transmitter a-methyldopamine, as well as by inhibition of AADC (Ch. 12). 

In contrast to a-methyldopa-induced hemolytic anemia, most drug-induced hemolytic anemia, especially for penicillins [34] and cephalosporins [35], involves drug-dependent antibodies, presumably because the drug acts as a hapten to directly modify erythrocytes or form immune complexes [36], However, there are many examples where a drug, such as nomifensine, induces both drug- (or metabolite)-dependent and drug-... 

Another drug that is associated with a relatively high incidence of both drug-de-pendent and autoimmune antibodies is diclofenac [38], In some cases the specificity of the diclofenac-induced autoantibodies is very similar to that induced by a-methyldopa [39], Diclofenac is a secondary aromatic amine and is oxidized to reactive metabolites by both cytochromes P450 and myeloperoxidase [40], When patient sera were tested, it was addition of the 4-hydroxy metabolite that most commonly led to agglutination of red cells [41] this metabolite has the potential to be air oxidized to a reactive iminoquinone. 

In addition, there is now good evidence indicating that methyldopa effectively suppresses the release of renin by the kidney(23,24). This effect may contribute to the antihypertensive efficacy of the drug in some hypertensive states in which the renin-angiotensin system plays a pathophysiologic role. Thus, it may be concluded that a) methyldopa lowers the blood pressure... 

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],... 

Dopamine antagonist activity is the hallmark of classical neuroleptics. The antihypertensive agents, reserpine (obsolete) and a-methyldopa, deplete neuronal stores of the amine. A common adverse effect of dopamine antagonists or depletors is parkinsonism. 

A potential versatile route into a-amino acids and their derivatives is via a combination of (i) nitrile hydratase/amidase-mediated conversion of substituted malo-nonitriles to the corresponding amide/acid followed by (ii) stereospecific Hofmann rearrangement of the amide group to the corresponding amine. Using a series of a,a-disubstituted malononitriles 14, cyanocarboxamides 15 and bis-carboxamides 16, the substrate specificity of the nitrile hydratase and amidase from Rhodococcus rhodochrous IF015564 was initially examined (Scheme 2.7). The amidase hydrolyzed the diamide 16 to produce (R)-17 with 95% conversion and 98%e.e. Amide 17 was then chemically converted to a precursor of (S)-a-methyldopa. It was found... 

Active transport of a particular substance occurs in one direction only. The number of molecules transported per unit of time will reach a maximum (T ,) once the binding capacity of the carrier becomes saturated. Drugs such as levodopa (for parkinsonism) and a-methyldopa (for hypertension) are actively transported. 

Metyrosine (Demser) is an example of this class of drugs. Chemically, metyrosine is a-methyl tyrosine. The drug blocks the action of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. Unlike a-methyldopa, metyrosine is not itself incorporated into the catecholamine synthetic pathway. The ultimate action of the drug is to decrease the production of catecholamines. 

Two important antihypertensive agents, a-methyldopa and clonidine, act predominantly in the brain (Fig. 20.2D). Although the details of their actions may differ in some respects, their antihypertensive activity is ultimately due to their ability to decrease the sympathetic outflow from the brain to the cardiovascular system. 

The spectrum of activity of a-methyldopa (Aldomet) lies between those of the more potent agents, such as guanethidine, and the milder antihypertensives, such as reserpine. a-Methyldopa is a structural analogue of di-hydroxyphenylalanine (dopa) and differs from dopa only by the presence of a methyl group on the a-carbon of the side chain. 

A number of theories have been put forward to account for the hypotensive action of a-methyldopa. Current evidence suggests that for a-methyldopa to be an antihypertensive agent, it must be converted to a-methyl-norepinephrine however, its site of action appears to be in the brain rather than in the periphery. Systemically administered a-methyldopa rapidly enters the brain, where it accumulates in noradrenergic nerves, is converted to a-methylnorepinephrine, and is released. Released a-methylnorepinephrine activates CNS a-adrenoceptors whose function is to decrease sympathetic outflow. Why a-methylnorepinephrine decreases sympathetic outflow more effectively than does the naturally occurring transmitter is not entirely clear. 

Approximately 50% of an orally administered dose of a-methyldopa is absorbed from the gastrointestinal tract. Both peak plasma drug levels and maximal blood pressure-lowering effects are observed 2 to 6 hours after oral administration. A considerable amount of unchanged a-methyldopa and several conjugated and de-carboxylated metabolites can be found in the urine. 

The primary hemodynamic alteration responsible for the hypotensive effects of a-methyldopa remains in dispute. A en the patient is supine, the reduction in blood pressure produced by a-methyldopa correlates best with a decrease in peripheral vascular resistance, cardiac output being only slightly reduced. When the patient is upright, the fall in blood pressure corresponds more closely with a reduced cardiac output. 

An important aspect of a-methyldopa s hemodynamic effects is that renal blood flow and glomerular filtration rate are not reduced. As occurs with most sympathetic depressant drugs and vasodilators, long-term therapy with a-methyldopa leads to fluid retention, edema formation, and plasma volume expansion. While data conflict somewhat, it is generally thought that a-methyldopa suppresses plasma renin activity. 

The presence of a-methyldopa and its metabolites in the urine reduces the diagnostic value of urinary catecholamine measurements as an indicator of pheochro-mocytoma, since these substances interfere with the fluorescence assay for catecholamines. 

The most commonly encountered side effects of a-methyldopa are sedation and drowsiness. These CNS effects are probably the result of reductions in brain catecholamine levels. Other side effects, also typical of sympathetic depression, are dry mouth, nasal congestion, orthostatic hypertension, and impotence. 

Autoimmune reactions associated with a-methyldopa treatment include thrombocytopenia and leukopenia. Since a few cases of an a-methyldopa-induced hepatitis have occurred, the drug is contraindicated in patients with active hepatic disease. FluUke symptoms also are known to occur. 

It is generally agreed that clonidine acts in the same general area in the brain as does a-methyldopa, that is, somewhere in the medulla oblongata. The principal difference between clonidine and a-methyldopa is that clonidine acts directly on a2-receptors, whereas a-methyldopa first must be converted by synthetic enzymes to a-methylnorepinephrine. 

---