Methyl-DOPA from

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. 

CATECHOL-O-METHYLTRANSFERASE INHIBITORS Catechol-O-Methyltrans-ferase (COMT) metabolizes levodopa as well as dopamine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine (from dopamine) (Figure 20-7). Approximately 99% of an orally administered dose of levodopa does not reach the brain but, rather, is decarboxylated to dopamine, which causes nausea and hypotension. Addition of an AAD inhibitor (e.g., carbidopa) reduces the formation of dopamine but increases the fraction of levodopa that is methylated by COMT. COMT inhibitors will block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma tj j of levodopa as well as the fraction that reaches the CNS. 

Why is it absolutely necessary to isolate the L-a-Methyl-dopa from the racemate Explain. 

It is generally aeeepted that COMT is an extraeellular enzyme in the CNS that catalyses the transfer of methyl groups from S-adenylmethionine to the meta-hydroxy group of the eateehol nueleus. Until recently the only inhibitors of this enzyme were pyragallol and eateehol whieh were too toxic for clinical use. Now other inhibitors have been developed, e.g. entaeapone and tolcapone, but these are used mainly to protect dopa (also a catecholamine) from O-methylation, in the treatment of Parkinson s disease (Chapter 15). 

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. 

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)... 

Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA (1965) Failure of reserpine to deplete noradrenaline neurons of alpha-methylnoradrenaline formed from alpha-methyl dopa. Acta Pharmacol Toxicol (Copenh) 22 270-276. 

There is evidence that quinone methides form as intermediates in the metabolic oxidation of catechol derivatives, a key step in a variety of biosynthetic processes such as melanization and sclerotization of animal cells. Tyrosinase from mushrooms catalyzes the oxidation of a-methyldopa methyl ester 54a. It has been proposed that this reaction observed in vitro is part of a metabolic pathway for the metabolism of 54a. This reaction proceeds by oxidation of ct-methyl dopa methyl ester 54a to give 54b, which cyclizes and is further oxidized to quinone methide 54c (Scheme 26).101 This quinone methide was identified by comparison to authentic 54c, which was prepared by chemical oxidation of 54a to 54c.102... 

Plasma and urine samples from atherosclerotic and control rats were comparatively analyzed by ultrafast liquid chromatography coupled with ion trap-time-of-flight (IT-TOF) MS (UFLC-IT/TOF-MS) (16). They identified 12 metabolites in rat plasma and 8 metabolites in rat urine as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcar-nitine, butyrylcamitine, propionylcamitine, and spermine in plasma and 3-0-methyl-dopa, ethyl /V2-acety I -1. -argininate, leucylproline, glucuronate, A(6)-(A-threonylcarbonyl)-adenosine, and methyl-hippuric acid in urine were decreased in atherosclerosis rats ursodeoxycholic acid, chenodeoxycholic acid, LPC (06 0), LPC (08 0), and LPC (08 1) in plasma and hippuric acid in urine were increased in atherosclerosis rats. The altered metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids, and amino acids. Lysophosphatidylcholine (LPC) plays an important role in inflammation and cell proliferation, which shows a relationship between LPC in the progress of atherosclerosis and other inflammatory diseases. 

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. 

The synthesis of L-methyl DOPA 80 by the Strecker reaction was straightforward and of course produced racemic material. A conventional resolution by crystallising the menthyl ester 83 from hexane and hydrolysis of acetal, ester and amide in 48% HBr (note that no racemisation by enolisation can occur) gives good yields.19... 

Several substituted histidines Table 4.8) have been tested as inhibitors of the histidine decarboxylase of guinea-pig kidney . From a consideration of the potencies of the substances tested, it was suggested that increasing the acidity of the nitrogens of the imidazole ring tended to produce stronger inhibitors. Similar studies on the inhibition of histamine formation by compounds related to DOPA or 5-HTP Table 4.8) showed that a-methyl-DOPA and DOPA are good inhibitors only the L-form of a-methyl-DOPA is an effective inhibitor of n-amino acid decarboxylase . The... 

Inhibition of Specific Histidine Decarboxylase The effect of inhibitors on specific histidine decarboxylase differs in certain important respects from their effect on non-specific histidine decarboxylase. In particular, the specific enzyme, unlike the non-specific enzyme, is scarcely affected by a-methyl-DOPA " >i i i . Conversely, the specific enzyme is subject to moderate inhibition by a-methylhistidine at concentrations which... 

Compounds MK 785 (XXVI) and MK 485 (XXVII), the a-hydrazino analogues of histidine and a-methyl-DOPA respectively, have been compared as inhibitors of the specific decarboxylase from foetal rats and the... 

Among the numerous variations made around the a-methyl-DOPA molecule, acylation with a glycyl-glycyl residue was claimed to improve oral bioavailability. For a series of anticandidal di- and tripeptides containing m-fluorophenylalanine (m-FPhe), competitive antagonism studies supported peptide transport-mediated entry of the warhead m-FPhe inside the cell. Dipeptides derived from a-methyldopa (Fig. 33.9) show a 10 to 20-fold better penetration of the intestinal wall than a-methyldopa itself. 

Alpha-methyl- DOPA (Aldomet) Decarboxylated to a-methyl dopamine then (3-hydroxylated to a-methyinorepinephrine, a potent a2 receptor agonist. Results in 4 mpathetic outflow from CNS. preganglionic sympathetic output, rapidly 4 blood pressure -but sympathetic system can respond with cardiac stimulation. Sedation, mild orthostatic hypotension, dry mouth, fever, nasal stuffiness, Coombs positive RBCs, salt and water retention, rebound hypertension. 

DSM has also succeeded in reacting a-branched amino acid amides with peptidases from Mycobacterium neoaurum. By this method, compounds such as the antihypertonic (L)-a-methyl-3,4-dihydroxyphenylalanine ((L)-a-methyl-DOPA) are accessible. For very similar transformations, Ube (Japan) has used amidases from Pseudomonasfluorescens. [64]... 

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