4-Hydroxy-3-methoxy-mandelic acid

Methoxy-4-hydroxy-mandelic acid Vanillylmandelic acid (VMA)... 

Catecholamines can be variously oxidized or methylated. Extracellular epinephrine is O-methylated [via liver catechol-O-methyltransferase (COMT)] to 3-methoxyepinephrine (metanephrine) which can thence be oxidized [via monoamine oxidase (MAO)] to 3-methoxy-4-hydroxy-mandelic aldehyde and thence to 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxy-mandelic. acid (VMA). Similarly, extracellular norepinephrine is O-methylated [via liver COMT] to 3-methoxynorepinephrine (normetanephrine) which can be oxidized [via MAO] to 3-methoxy-4-hydroxy-mandelic... 

Norepinephrine (NE) is taken up into the nerve terminus of the adrenergic neuron by neuronal reuptake mechanisms ( pumps ). It is then degraded intracellularly, by monoamine oxidase (MAO) (primarily MAOa, a mitochondrial enzyme) to form dihydroxymandelic acid. This is further inactivated by the tissue enzyme catechol-O-methyl transferase (COMT). Transmitter remaining in the synaptic cleft is rapidly degraded, first by COMT, located on postsynaptic membranes, to form normetanephrine. This in turn is taken into the neuron and converted to 3-methoxy, 4-hydroxy mandelic acid (VMA) through the actions of MAO (see Figure, top of next page). 

Epinephrine is ultimately metabolized by COMT and MAO to 3-methoxy-4-hydroxy-mandelic acid (vanillylmandelic acid), which is excreted as the sulfate or glucuronide in the urine (Fig. 44.5). 

Catechol-O-methyltransferase from rat liver requires S-adeno-sylmethionine as a methyl donor and can methylate catechol but not monohydroxy derivatives of phenylethylamine. In vivo, O-methylation occurs exclusively in the meta position to the carbon side chain, but with purified preparations of the enzyme in vitro methylation can lead to both meta and para methylation. The ratio of products is susceptible. to both the polarity of the substrate and the pH of the medium . In man 3-methoxy-4-hydroxy-mandelic acid (18) comprises about 40 per cent of the total urinary metabolites produced from the catecholamines whilst in other pecies 3-methoxy-4-hydroxyphenylglycol (19), isolated as a sulphate ester, is the predominant breakdown product . A typical metabolic grid which indicates the possible types of pathway leading from noradrenalin (17) to both of these metabolites is shown in Figure 4.4 analogous metabolic schemes may be drawn up for both adrenalin and dopamine. 

Maltol — see Pyran-4-one, 3-hydroxy-2-methyl-Maltol, ethyl — see Pyran-4-one, 3-ethoxy-2-methyl-Maltol, methyl — see Pyran-4-one, 3-methoxy-2-methyl-Mandelic acid ethyl ester, 1, 310-311 Manganaindene reactions, 1, 671 Mannich bases dehydro... 

COMT = Catechol-O-Methyl transferase MAO = Monoamine Oxidase HMMA = Hydroxy Methoxy Mandelic Acid... 

Levarterenol (I) is methylated by catechol 0-methyl transferase giving normeta-neph ri ne (11). 2 7 2 8 Deamination of II to an aldehyde intermediate and oxidation or reduction of the aldehyde leads to 4-hydroxy-3-methoxy-phenylglycol (III), or 4-hvdroxy-3-methoxy-mandelic acid (IV).25,26,28... 

This is a misnomer, but because of its popularity the name VMA has been retained in this publication. In many publications it is being referred to as 4-hydroxy-3-methoxy mandelic acid. 

A16. Armstrong, M. D., McMillan, A., and Shaw, K. N. F., 3-Methoxy-4-hydroxy-D-mandelic acid, a urinary metabolite of norepinephrine. Biochim. et Biophus. Acta 26, 422 (1957). 

Catecholamines and their metabolites The catecholamines, adrenaline, noradrenaline, and dopamine are essential components of the central nervous system acting as neurotransmitters both within the brain and at peripheral nerves. All are synthesized in the adrenal medulla from phenylalanine or tyrosine and are metabolized by a mixture of enzymatic side chain oxidation and methylation of the hydroxy groups on the ring. If the metabolism is complete, adrenaline and noradrenaline are degraded to 4-hydroxy-3-methoxy mandelic acid (HMMA, commonly called vanillylmandelic acid - VMA), while dopamine is broken down to homovanillic acid (HVA). Urinary excretion of these metabolites and their conjugates is the major route of elimination of catecholamines from the body, although small amounts are excreted unchanged as the free catecholamines. 

An aq. soln. of glyoxylic acid monohydrate added dropwise during 4 hrs. at 0-5° to a stirred mixture of guaiacol and aq. NaOH, and stirring continued 20 hrs., while the temp, is allowed to rise to ca. 20° DL-4-hydroxy-3-methoxy-mandelic acid. Y 65-75%. A. J. Fatiadi and R. Schaffer, J. Research Nat. Bur. Standards 78A, 411 (1974). 

Hydroxy-3-methoxy> mandelic acid 4-Hydroxy-3-meihoxy-mandelic aldehyde... 

Continuous production of (/ )-mandelic acid in an enzyme membrane reactor was reported by Kula et al. [122]. a-Hydroxy esters can be obtained from these acids in the usual ways. They are also accessible directly from the cyanohydrins by a modified Pinner synthesis conversion in diethyl ether, in the presence of 2 equivalents of the alcohol and 2 equivalents of HCl gas, affords the iinidate salt (Scheme 10). By dissolving this salt in water, it is rapidly and quantitatively converted to the corresponding ester [46,98]. If R-cyanohydrins of p-substituted pivaldehydes, like -methoxy- or P-chloropivaldehyde, are hydrolized with concentrated HCl, (jR)-pantolactone is obtained in good yield and high enantiomeric excess [103] (Scheme 11). 

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