Methyltyrosine, a

Metyrosine Metyrosine, (-)a-methyltyrosine (12.3.11), is synthesized in a few different ways, the simplest of which is the synthesis from 4-methoxybenzylacetone, which is reacted with potassium cyanide in the presence of ammonium carbonate to give the hydan-toin (12.3.9). Treating this with hydrogen iodide removes the methyl-protecting group on the phenyl hydroxyl group and the product (12.3.10) is hydrolyzed by barium hydroxide into a racemic mixture of a-methyl-D,L-tyrosine, from which the desired L-isomer is isolated (12.3.11) [83-86]. 

Dopamine synthesis inhibitors interfere with the enzymes involved, and are identical to those discussed in section 4.3.5 (e.g., a-methyltyrosine (4.74), a tyrosine hydroxylase inhibitor). In this case, aj-adrenergic receptor effects are irrelevant, and only the classical competitive inhibitory effect is of any consequence. 

The prevalent Microcystis aeruginosa has afforded the plasmin inhibitors micropeptins 478-A (1115) and 478-B (1116) (1133). The terrestrial cyanobacterium Scytonema hofmanni PCC 7110 gives rise to scyptolins A (1117) and B (1118), which contain the 3-chloro-A-methyltyrosine residue (1134). The binding of 1117 to pancreatic elastase has been determined by X-ray crystallography (1135). Myriastramide B (1119) was isolated from the Philippine sponge Myriastra clavosa and features a novel chlorinated ether moiety (1136). 

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

Chemical Name 0-(4-Hydroxy-3,5-diiodophenyl)-3,5-diiodo-a-methyltyrosine ethyl ester... 

FIGURE 12. Clonogenic survival of B16 melanoma cells exposed to 211At-labelled a-methyltyrosine for 45-min incubation period. 1 pCi = 37 Bq. Reproduced by permission of Academic Press from Reference 123... 

The TIDA neurons are activated by prolactin. This was first shown by Hokfelt and Fuxe (1972) when they demonstrated that systemic administration of this hormone to rats increased the a-methyltyrosine-induced decline in DA histofluorescence exclusively in the median eminence. Subsequent investigators using quantitative biochemical procedures have demonstrated that systemic and ventricular injections of prolactin increase the activity of TIDA, but not other DA neurons (Moore, 1987b). There is a delay of 12-16 h before the actions of prolactin became evident and at least part of the delay appears to be secondary to processes that involved alterations in gene expression and protein synthesis. 

The majority of experimental evidence supports the conclusion that bombesin-like peptides stimulate the activity of TIDA neurons and thereby inhibit pituitary prolactin secretion. Indeed, bombesin administration does not suppress a-methyltyrosine- or haloperidol-induced prolactin secretion suggesting that pharmacological impairment of TIDA neuronal function prevents the prolactin inhibitory actions of bombesin (Collu et al., 1983 Buydens et al., 1988). Moreover, bombesin-like peptides block both opiate -and stress-induced prolactin secretion (Tache et al., 1979 Matsushita et al., 1983 Buydens et al., 1988), prolactin secretory responses known to be due, at least in part, to suppression of the activity of TIDA neurons (Moore and Lookingland, 1995). Central administration of bombesin increases DA synthesis and metabolism in whole hypothalamus (Widerlov... 

Metirosine (a-methyltyrosine) has been used with some success to block catecholamine synthesis in malignant phaeochromocytomas. 

Nomifensin Clla) is an antidepressant which produces significant DA-mimetic motor effects in animal models.It has now been shown that the catechol analog 11c is a potent agonist (0.25-0.50 x DA) on the adenylate cyclase from both striatum and nucleus accumbens, whereas 11a and 11b are inactive.Another group has shown that 11c is potent in inducing stereotyped behavior upon injection into the nucleus accumbens. Because this effect was blocked by a-methyltyrosine pretreatment, a presynaptic mode of action was inferred. The related compound lid has shown limited clinical efficacy in the treatment of Parkinson s disease. 

Saari, W.S., Halczenko, W., Cochran, D.W., et al. (1984) 3-Hydroxy-a-methyltyrosine progenitors synthesis and evaluation of some (2-oxo-l,3-dioxol-4-yl)methyl esters. J. Med. Chem. 27 713-717. 

By hydrolysis of RA-VII (166), one D-alanine, two molecules of L-alanine, A-methyl-4-methoxy-L-phenylalanine, and A-methyltyrosine dimer having an ether linkage were obtained. The isolate was assumed to be a cyclic hexapeptide consisting of three alanine and three tyrosine molecules. From these findings, the structure of RA-VII was assumed to be a bicyclic hexapeptide having an ether linkage. However, it was difficult to decide the sequence of amino acids and the configuration stereochemically. Finally, X-ray analysis was applied to the p-bromobenzoate of RA-V (164). 

The presently known cactus alkaloids are of simple chemical constitution. They are either substituted /3-phenethylamines, evidently related to and probably derived from the naturally occurring aromatic amino acids (tyrosine, dihydroxyphenylalanine, A -methyltyrosine, etc.), or they are simple tetrahydroisoquinolines that could originate from these bases by condensation and cyclization through the action of organic compounds containing one or two carbon atoms (formaldehyde and acetaldehyde equivalents ). 

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