A-Methyl dopa

Nitroethane. The principal use of nitroethane is as a raw material for synthesis in two appHcations. It is used to manufacture a-methyl dopa, a hypertensive agent. Also, the insecticide 3 -methyl-A/-[(methylcarbamoyl)oxy]thioacetimidate [16752-77-5] can be produced by a synthesis route using nitroethane as a raw material. The first step of this process involves the reaction of the potassium salt of nitroethane, methyl mercaptan, and methanol to form methyl methylacetohydroxamate. Solvent use of nitroethane is limited but significant. Generally, it is used in a blend with 1-nitropropane. 

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

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.

The noradrenaline normally contained in the storage granules can be partly or completely replaced by structurally related sympathomimetic amines, either by injection of the amine itself, or of suitable precursors such as a-methyl-DOPA or a-methyl-w-tyrosine. These amines can be depleted from the heart by guanethidine in the same way as the noradrenaline which they had replaced. a-Methylnoradrenaline [337] and metaraminol [338] are depleted less readily than noradrenaline from rabbit or rat hearts, whereas dopamine, octopamine and w-octopamine are depleted more readily than noradrenaline [339]. The more rapid depletion of these last three compounds was attributed to weaker binding in the storage granules [339], but could equally well be due to their greater susceptibility to destruction by monoamine oxidase, since both a-methyl-noradrenaline and metaraminol are resistant to attack by monoamine oxidase. 

A number of 2,3-methanophenylalanine derivatives are efficient inhibitors of DOPA carboxylase [64]. For instance, 2-(3,4-dihydroxyphenyl) ACC 57, due to its structural analogy with a-methyl DOPA 58, is a reversible time-dependent inhibitor of DOPA carboxylase and of tyrosine amino transferase, Eq. (22) [65]. 

P35 Pivaldehyde and 3,4-dimethoxyphenylacetone were used as starting materials, which lead, respectively, to enantiomerically enriched tert-leucine and a-methyl-dopa, two important nonproteogenic a-amino acids for pharmaceutical applications. In addition, tert-leucine has considerable utility as a chiral building block.(From Boesten et ah, 2001)... 

After oral ingestion the prodrug a -methyl-DOPA is converted into its active metabolite a-methylnorad-renaline, a rather selective a 2-adrenoceptor stimulant. Accordingly, a-methyl-DOPA via its active metabolite causes peripheral sympathoinhibition as a result of 2-adrenoceptor stimulation in the brain stem. a-Methyl-DOPA is an effective antihypertensive, which has been used on a very large scale for decades. Its efficacy and safety are beyond doubt. It is one of the very few drugs which are known to be... 

In summary, a-methyl-DOPA may be considered as a second choice antihypertensive. In spite of this it is still used on a moderately large scale in certain countries because of its low cost. Its documented safety in pregnant women explains why it is sometimes used by obstetricians in such patients. 

Tricyclic antidepressants potentiate the pressor effects of directly acting sympathomimetic amines, such as adrenaline (epinephrine) or noradrenaline (norepinephrine), to cause hypertension. Small amounts of these, such as may be present in local anaesthetic solutions, can be dangerous. Tricyclic antidepressants will inhibit the antihypertensive effects of the older anti hypertensive drugs, such as adrenergic neurone-blocking agents, e.g. guanethidine, a-methyl-DOPA, and clonidine. 

A two-electron oxidation of N-acetyltyrosine ethyl ester with mushroom tyrosinase, or with periodate, afforded the N-acetyIdopa ester 142, together with the (Z)-enamide 145 and the 6-acetoxydopa amide 146 (Fig. 40) (284). It is assumed that 145 originates from dopaquinone 143 via 144 by tautomerization. Michael addition of acetate to quinone 143 is believed to be the origin of 146. The formation of quinone methide 144 from dopa ester 142 by tyrosinase is reminiscent of the formation of iminochromes and quinone methides catalyzed by this enzyme in their formation from a-methyl dopa ester (285), and such reactions may well occur in mammalian systems. 

Another dmg closely similar to DOPA but used for different applications is a-methyl-DOPA (Figure 10.19a). This molecule acts in the peripheral autonomous system but also enters the brain, by the same route as DOPA. It is converted by DOPA decarboxylase to the false transmitter a-methyl-dopamine. Like dopamine or norepinephrine, a-methyl-dopamine is accumulated inside the transmitter vesicles, and released in response to action potentials. While it has no strong effect on postsynaptic a,-receptors, it does activate 0C2-receptors. It will therefore inhibit the further release of transmitter without stimulating the postsynaptic neuron. The effect of methyl-DOPA is augmented by the fact that it is fairly resistant to monoamine oxidase. Its mode of action resembles that of clonidine (which accomplishes the same in a less roundabout manner). 

Alkylations of the Lithium Enolates. Treatment of the reagents with Lithium Diisopropylamide (LDA) generates the enolates (2) or ent- 2) (crystal structure of rac-TBDMS-(2) ) which can be alkylated to give, for instance, (/ )-a-methyl-dopa (3) or triacetyl (S)-a-methyl-dopa. ... 

Proof of enantiomeric purity is necessary in the case of L-3,4-dihydroxyphenylalanine (L-DOPA), a drug used to treat Parkinson s disease, because of the high toxidty of the D enantiomer. Previously, D,L-DOPA was resolved by Frank, Nicholson, and Bayer using Chirasil-val (41). Figure 6 shows the separation of D, L-DOPA on a column with per-pentylated ot-cydodextrin. In the case of a-methyl-DOPA (Aldomet) [4], a drug that is used in its L form for its antihypertensive activity, the enan-... 

PA Porter, I Osiecka, RT Borchaidt, JA Fix, L Frost, CR Gardner. In vitro drug absorption models II salicylate, cefoxitin, a-methyl dopa, and theophylline uptake in cells and rings correlation with in vivo bioavailability. Pharm Res 2 293—298,1985. 

Sjoerdsma, J., Udenfriend, S. Pharmacology and biochemistry of a-methyl-dopa in man and experimental animals. Biocherm Pharmacol. 1961, 8, 164. 

Among the numerous variations made to a-methyl-dopa, acylation with a glycyl-glycyl residue was claimed... 

Benzodiazepines - A supraspinal site of action has been demonstrated for chlordiazepoxide and diazepam as well as for meprobamate.88 xhe anticonvulsant action of chlordiazepoxide resembles that of dilantin instead of that of acetazolamide, being antagonized by reserpine but not by 0 -methyl DOPA or Ct-methyltyrosine.89 This antagonistic effect of reserpine is reduced by a-methyl DOPA, serotonin and amphetamine. The reserpine effect is thus obtained by some means other than its catecholamine-depleting action and the anticonvulsant action of chlordiazepoxide is not mediated by catecholamines. 

Some interesting comparisons ha e been drawn between the characteristic actions of Catapresan and reserpine, a-methyl-dopa and guanethidine. Similarities and distinctions were noted in each case. The conclusion was reached that the mechanism of action of Catapresan has not, as yet, been clarified and the drug has characteristics such that it cannot be adequately classified in any of the known drug groups now used in antihypertensive therapy. ... 

Figure 10. Metabolites of a-methyl DOPA which could act as false neurotransmitters. a-Methyl DOPA acts in the form of its decarboxylated...

We have already discussed the use of DOPA and a-methyl DOPA as the protected precursors of the active amine metabolites and resorting to the use of DOPA decarboxylase inhibitors in making possible the administration of greatly lowered doses of the none-too-innocuous DOPA. 

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