5- Hydroxy-dopa

Various hydroxyl and amino derivatives of aromatic compounds are oxidized by peroxidases in the presence of hydrogen peroxide, yielding neutral or cation free radicals. Thus the phenacetin metabolites p-phenetidine (4-ethoxyaniline) and acetaminophen (TV-acetyl-p-aminophenol) were oxidized by LPO or HRP into the 4-ethoxyaniline cation radical and neutral V-acetyl-4-aminophenoxyl radical, respectively [198,199]. In both cases free radicals were detected by using fast-flow ESR spectroscopy. Catechols, Dopa methyl ester (dihydrox-yphenylalanine methyl ester), and 6-hydroxy-Dopa (trihydroxyphenylalanine) were oxidized by LPO mainly to o-semiquinone free radicals [200]. Another catechol derivative adrenaline (epinephrine) was oxidized into adrenochrome in the reaction catalyzed by HRP [201], This reaction can proceed in the absence of hydrogen peroxide and accompanied by oxygen consumption. It was proposed that the oxidation of adrenaline was mediated by superoxide. HRP and LPO catalyzed the oxidation of Trolox C (an analog of a-tocopherol) into phenoxyl radical [202]. The formation of phenoxyl radicals was monitored by ESR spectroscopy, and the rate constants for the reaction of Compounds II with Trolox C were determined (Table 22.1). 

Fig. 1. Prosthetic groups in oxidases (A FAD B Thio-Tyrosine C NAD(P) + D 6-Hydroxy-DOPA E Methoxanthin (Pyrroloquinoline quinone PQQ) F Tryptophane-Tryptophan quinone)...

Amine oxidase [EC 1.4.3.6] (also known as diamine oxidase, diamino oxhydrase, and histaminase) catalyzes the reaction of an organic amine (i.e., R—CH2—NH2) with dioxygen and water to yield an aldehyde, ammonia, and hydrogen peroxide. Cofactors are a copper ion and 6-hydroxy-DOPA. 

Structure of the active center. The active centers of this dimeric enzyme are so well embedded into its protein structure that they are inaccessible to the solvent. The two centers are situated approximately 30 A apart from each other but connected by /3-strands. The active center consists of a type 2 copper center and a cofactor. Sequence comparisons have established that the residues His 8, His 246, and His 357 coordinate the copper ions in both yeast and plants (e.g., lentil seeds) [120,122]. The participating cofactor is typical for amine oxidases, diamine oxidases, and lysyl oxidases but has not yet been found in any other protein - 2,4,5-trihydroxy-phenylalanine quinone [123, 124] (also known as TOPA-quinone, TPQ or 6-hydroxy-DOPA quinone), an internal cofactor which is created by post-translational modification of the tyrosine in position 387 [120]. The consensus sequence of the amino acids neighboring the TOPA cofactor are conserved in all known amine oxidases - Asn-TOPA-Asp/Glu [113,120, 123,125-127]. The positions of the histidine ligands relative to TOPA quinone are conserved in all known amine oxidases as well. The chain lengths of the amine oxidase monomers vary according to the organism of origin 692 residues in yeast [128], 762 in bovine serum amine oxidase [128,129] and 569 in the enzyme from lentil seeds [120,130]. 

The amount of vanadium found in tunicates also appears to correlate with the pH (more vanadium at lower pH). Individuals belonging to the Phiebobranchia usually also contain tunichromes, whereas Apiousobranchia are devoid of this hydroxy-DOPA-based oligopeptide pigment (see below). The vanadium is present in special blood cells, called vanadocytes, essentially represented by two cell types the signet ring cells and the vacuolated amoebocytes.P 1 They accumulate vanadium from sea water [c(V) >= 30 nm] by a factor of up to 10. ... 

According to Thoenen et al. [249], 5-hydroxy dopa gives rise to marked norepinephrine depletion in the cat. Its 0-methyl derivative, 4-methoxy-3,5-dihydroxyphenylalanine, exerts a hypotensive effects in animals [245,250]. 

FIGURE 27 5 Tyrosine is the biosynthetic precursor to a number of neurotransmit ters Each transformation IS enzyme catalyzed Hydroxy lation of the aromatic ring of tyrosine converts it to 3 4 dihyd roxyphenylalanine (l dopa) decarboxylation of which gives dopamine Hy droxylation of the benzylic carbon of dopamine con verts It to norepinephrine (noradrenaline) and methy lation of the ammo group of norepinephrine yields epi nephrine (adrenaline)... 

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). 

Figure 1. Biosynthetic pathways for biogenic amines. In Drosophila and vertebrates decarboxylation of DOPA and 5-hydroxy-tryptophan is catalyzed by the same enzyme, DDC. In vertebrates this enzyme is called amino acid decarboxylase (AADC). Only vertebrates further metabolize dopamine to norepinephrine and epinephrine. TH, tryosine hydroxylase DDC, DOPA decarboxylase DBH, dopamine b-hydroxylase PNMT, phenylethanolamine N-methyltransferase. Tryp-OH tryptophan hydroxylase.

Y Tsuchiya, Y Sawasaki, A Hsako, H Takehana, K Tomimoto, M Yano. New potential prodrug to improve the duration of L-dopa L-3-(3-Hydroxy-4-pivaloyl-oxyphenyl) alanine. J Pharm Sci 78(7) 525-529, 1989. 

One must be careful not to generalize from the above discussion that hydrolysis of pivaloyl esters will always be slow. Indeed, a notable exception may well exist for monoesters of catechols, where intramolecular catalysis accelerates hydrolysis. This was seen for L-3-[3-hydroxy-4-(pivaloyl-oxy)phenyl] alanine (8.81 4-pivaloyl-L-dopa), a potentially valuable prodrug of L-dopa [114], When given to rats and dogs, 4-pivaloyl-L-dopa displayed markedly longer duration of action and a higher bioavailability of L-dopa than the drug itself complete conversion to L-dopa was noted in rat. The... 

N. Takenaga, A. Hisaka, M. Ohtawa, Differential Effects of L-3-(3-Hydroxy-4-pivaloyl-oxyphenyl)alanine (NB-355) and L-Dopa in the Striatum of Freely Moving Rats , Biogenic Amines 1992, 9, 7-13. 

This enzyme [EC 4.1.1.28] (also referred to as DOPA decarboxylase, tryptophan decarboxylase, and hydroxy-... 

Hydroxy-3-methoxy-L-phenylalanine reacts with xenon difluoride to form after acidic hydrolysis by hydrogen bromide 6-fluoro-3,4-hydroxy-i.-phenylalanine (6-F-DOPA) in 25 % yield.66... 

The 216-residue hen egg yolk storage protein phosvitin contains 123 serine residues, most of which have been phosphorylated (Eq. 2-16).295 A basic protein of the myelin sheath of neurons contains as many as 6 specific residues of citrulline (Eq. 2-19).296 An adhesive protein from the foot of a marine mollusk contains -80 repeated sequences containing hydroxy-proline 2,3-dihydroxyproline and 3,4-dihydroxyphenylalanine (Dopa) 297/298... 

These also presumably lead to a transient quinonoid-carbanionic intermediate. Addition of a proton at the original site of decarboxylation followed by breakup of the Schiff base completes the sequence. Decarboxylation of amino acids is nearly irreversible and frequently appears as a final step in synthesis of amino compounds. For example, in the brain glutamic acid is decarboxy-lated to y-aminobutyric acid (Gaba),193 196b while 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxy-... 

Fig. 30-27). The fact that L-tryptophan has some antidepressant activity, but L-dopa does not, was one clue that a low concentration of serotonin (5-hydroxy-tryptamine) might be responsible for depression. Excessive formation of histamine1099 and decreased formation of tyramine and octopamine1100 have also been suggested as causes of depression. 

Wulff and his collaborators reported, in 1989, the preparation of imprinted polymers able to perform enantioselective synthesis [11, 12]. The imprinting complex was prepared by reacting 3,4-di-hydroxy-phenyl-alanine methyl-ester (l-DOPA methyl ester) (16) with the 4-vinyl-salicylaldehyde (17) to form the corresponding Schiff s base (18), which was further reacted with the 4-vinyl-phenyl-boronic acid (19) to afford to the corresponding ester (20) (Scheme 4). The imprinting complex obtained was then polymerised and the template removed. The resulting polymers were incubated with sodium glycinate to allow formation... 

Typical probes for the analysis of ionic solutes include 3-hydroxy-L-tyrosine (DOPA)24 and naphthalene-2-sulfonate,26 whereas those for use with uncharged solutes include nicotinamide,27 theophylline,28 and anthracene 29 Indirect detection is nonspecific and less suitable for the analysis of complex or impure samples, because unpurified biological samples, such as urine, contain a large number of hydrophilic solutes that will give problems such as extra system peaks. However, analyses of pharmaceutical products and quantification of impurities in substances are typical of applications.23... 

Phenylethylamine deriva- Nucleosil 5C8, 3 pm tives (epinephrine, DOPA, 2-amino-3-hydroxy-3-phenyl-propanol, ephedrine)... 

In a similar context, 6-18F-3,4-dihydroxyphenylalanine (6-18F-DOPA) was synthesized by direct fluorination of L-3-(3-hydroxy-4-pivaloxyphenyl)alanine (ra-P-DOPA) with Ac018F in acetic acid resulting in the 2- and 5-18F isomers. Hydrolysis of the reaction mixture in hydrochloric acid followed by HPLC separation gave 6-18F-DOPA (equation 23)44. Another application of Ac018F was reported in the synthesis of a trimethyl tin precursor of 2-oxoquazepam, 7-chloro-1 -(2,2,2-trifluoroethyl)-1,3--dihydro-5-(2-fluorophenyl)-2//-l,4-benzodiazepin-2-one, a benzodiazepine agonist, and its conversion to [18F]-2-oxoquazepam by reaction with AcQ18F (equation 24)45. 

Dopamine may alternatively be formed from tyrosine via hydroxylation of L-dopa which is decarboxylated. However, inverse isotope dilution experiments to study the formation of dopamine and dopa have shown that this is probably a minor pathway in peyote (176). It has been shown that L-tyrosine is incorporated into alkaloids in peyote three times more efficiently than into protein (344). 4-Hydroxy-3-methoxyphenethylamine can be methylated to 3,4-dimethoxy-phenethylamine (homoveratrylamine), which may be viewed as a dead-end product in Scheme 2 (10, 203). Phenylalanine is probably not a precursor of the... 

---