5 -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. 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

Colorimetric procedures used In steroid assays are often subject to drug Interference. In the determination of 17-Ketosterolds by the Zimmerman reaction, drugs with the 17-Keto basic structure such as ascorbic acid, morphine and reserplne will cause Increased values. In the determination of 17,21 -dlhydroxysterolds by the Porter-Sllber reaction the dlhydroxy-acetone chain Is the reactive unit. Drugs like meprobamate, chloral hydrate, chloropromazlne and potassium Iodide will Interfere with this reaction and cause elevated values. In the colorimetric determination of vanlllylmandellc acid (VMA) by a dlazo reaction, drugs like methocarbamol and methyl dopa cause... 

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 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

Central a2-Agonists Methyl dopa Clonidine (Catapres) Guanabenz Guanfacine (Tenex) Guanadrel No recommendations at this time Transient sedation initially First-line in pregnancy (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.

Destruction of central adrenergic neurons by intraventricular injection of 6-hydroxydopamine (6 OHDA) virtually abolished the hypotensive effect of methyl-dopa. Adrenergic neurons are probably required to con-... 

Thyroid supplement Blood pressure medications Beta blockers Thiazide diuretics Alpha methyl DOPA Appetite suppressants Phentermine Sibutramine Other Alcohol Caffeine Cocaine Nicotine... 

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)... 

Moxonidine and rilmenidine are the only examples of moderately selective Ii-receptor stimulants which have been developed clinically. Since moxonidine and rilmenidine have much lower affinity for a 2-receptors than for Ii-receptors it may be hoped that they will display a more favourable pattern of side-effects than classic o 2-adrenoceptor stimulants such as clonidine, guanfacine and Q -methyl-DOPA. 

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. 

Methyldopa (Aldomet) and methyl dopa-hydrochloro thiazide (Aldoril) May cause bradycardia, and exacerbate depression in elderly patients. High... 

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. 

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