L-methyl DOPA

DSM has developed a general, industrial-scale process for the production of either l- or D-amino acids through the hydrolysis of the amide (Scheme 2.22).75 78 The product amino acid and untouched amide are easily separated. The amide can be recycled. The resolution method has been extended to a,a-disubstituted of which L-methyl-dopa (14) is an example.79... 

It should also be noted that at DSM this amidase process has been extended towards the synthesis of optically active a,a-disubstituted amino acids. For example, the antihypertensive drug L-methyl-dopa, l-10, has been produced successfully (Fig. 8) [14, 15]. 

The aromatic amino acid L-methyl DOPA (Di Hydroxy PhenylAlanine) 80 is used to make an antihypertensive compound. Synthesis by the Strecker method clearly requires the aromatic ketone 77, and the synthesis follows the pattern below.18 The intermediates and final product have been resolved in various ways. 

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... 

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. 

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.

Biosynthesis. The terminal C methyl of the propyl side chain, the S-methyl. and the /V methyl groups are derived from methionine, trans-4-Propyl-L-proline was shown to accumulate when Strepromyces lincolnensis is grown in media deficient in sulfur, and the addition of T. tyrosine or L-dihydroxyphenylalaiiine (DOPA) was shown to stimulate this production. 

FIGURE 23.7 Dopamine (DA) is synthesized within neuronal terminals from the precursor tyrosine by the sequential actions of the enzymes tyrosine hydroxylase, producing the intermediary L-dihydroxyphenylalanine (Dopa), and aromatic L-amino acid decarboxylase. In the terminal, dopamine is transported into storage vesicles by a transporter protein (T) associated with the vesicular membrane. Release, triggered by depolarization and entry of Ca2+, allows dopamine to act on postsynaptic dopamine receptors (DAR). Several distinct types of dopamine receptors are present in the brain, and the differential actions of dopamine on postsynaptic targets bearing different types of dopamine receptors have important implications for the function of neural circuits. The actions of dopamine are terminated by the sequential actions of the enzymes catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), or by reuptake of dopamine into the terminal. 

Pearce RKB, Jackson M, Smith L, Jenner P, Marsden CD (1995) Chronic L-DOPA administration induces dyskinesias in the l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine-treated common marmoset (Callithrix jacchus). Mov Disord 70 731—740. 

Harrison, W. H., Gray, R. H., and Solomon, L. M., Incorporation of L-dopa, L-alpha-methyl-dopa and DL-isoproterenol into guinea-pig hair, Acta Derm. Venereal, 54, 249, 1974. 

Quik M, VaUati S, Bordia T, Kulak JM, Fan H, McIntosh JM, Clementi F, Gotti C (2005) Subunit composition of nicotinic receptors in monkey striatum effect of treatments with l-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine or L-DOPA. Mol Pharmacol 67 32-41... 

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. 

Biosynthesis. The terminal C-methyl of the propyl side chain, the L-methyl, and the ZV-methyl groups are derived from methionine (19). /ftmf-4-Propyl-L-proline [51101-27-6] was shown to accumulate when Streptomyces lincolnensis is grown in media deficient in sulfur, and the addition of L-tyrosine or L-dihydroxyphenylalanine (DOPA) was shown to stimulate this production. From a comparison of the incorporation of label from L-[l-14C]tyrosine and l[U-14C tyro sine, it was demonstrated that all of the carbon atoms of the propylproline other than the C-terminal methyl group were derived from tyrosine and, by the use of L-[15N]tyrosine, it was determined that the proline nitrogen atom was derived from the amino—nitrogen atom of tyrosine (20). 

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... 

L-dopa can be metabolized by COMT to 3-methyl dopa. This metabolic pathway becomes active when neuronal pathways that convert dopa to dopamine are blocked by dopa decarboxylase... 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

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