3’-Methyl tyrosine

Catecholamine biosynthesis begins with the uptake of the amino acid tyrosine into the sympathetic neuronal cytoplasm, and conversion to DOPA by tyrosine hydroxylase. This enzyme is highly localized to the adrenal medulla, sympathetic nerves, and central adrenergic and dopaminergic nerves. Tyrosine hydroxylase activity is subject to feedback inhibition by its products DOPA, NE, and DA, and is the rate-limiting step in catecholamine synthesis the enzyme can be blocked by the competitive inhibitor a-methyl-/)-tyrosine (31). 

Chemical Name 0-(4-Hydroxy-3,5-dllodophenyl)-3,5-dliodo-0 -methyl tyrosine ethyl ester Common Name —... 

CifiHpNO, 33522-95-1) see Nalbuphine Naloxone 2 -hydroxy-4 -(2,5-dihydro-5-oxo-3-furyl)acetophenone (C12H10O4 3447-63-0) see Benfurodil hemisuccinate 0-(4-hydroxy-3,5-diiodophenyl)-3,S-diiodo-a-methyl-tyrosine... 

There are few reports on the effects of nitrous oxide on dopaminergic neurotransmission. A study in mice showed that nitrous oxide inhalation produced a significant increase in locomotor activity that was antagonized in a dose-dependent fashion by the dopamine synthesis inhibitor a-methyl-/)-tyrosine (Hynes and Berkowitz 1983). Moreover, administration of the D2 antagonist haloperidol also reduced the locomotor activity induced by nitrous oxide (Hynes and Berkowitz 1983). These results suggest that excitatory effects induced by nitrous oxide may be also mediated by dopaminergic neurotransmission. However, other studies have reported that exposure to nitrous oxide resulted in decreased dopamine release by neurons in the striatum (Balon et al. 2002 Turle et al. 1998). 

Cyclo(His-D-Leu) acts as a hydrolytic catalyst. Cyclo(Leu-Gly) blocks the development of (1) physical dependence on morphine, (2) tolerance to the pharmacological effects of /3-endorphin, (3) tolerance to haloperidol-induced catalepsy and hypothermia, and (4) dopaminergic supersensitivity after chronic morphine administration. Cyclo(Tyr-Arg), a synthetic analogue of kyortorphin (an endogenous analgesic peptide), and its A-methyl tyrosine derivatives are more potent than kyotorphin in the mouse tail pressure test. ... 

Rapid relapse following administration of the tyrosine hydroxylase inhibitor alpha-methyl-tyrosine to depressed patients who respond to a noradrenaline reuptake inhibitor such as desipramine... 

Metyrosine (Demser) is an example of this class of drugs. Chemically, metyrosine is a-methyl tyrosine. The drug blocks the action of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. Unlike a-methyldopa, metyrosine is not itself incorporated into the catecholamine synthetic pathway. The ultimate action of the drug is to decrease the production of catecholamines. 

Antagonists of the vasoconstrictor action of vasopressin are also available. The peptide antagonist (l-[B-mercapto-B,B-cyclopentamethylenepropionic acid]-2-[0 -methyl]tyrosine) arginine vasopressin also has antioxytocic activity but does not antagonize the antidiuretic action of vasopressin. Recently, nonpeptide, orally active Via receptor antagonists have been discovered, an example being relcovaptan. 

Resistance of inhibitors to gut proteolysis has been improved by various methods such as replacement of phenylalanine at P3 with O-methyl tyrosine (or naphthylalanine), which was shown to abolish chymotrypsin cleavage and yet retain high inhibitory potency for renin [40]. 

Methyl tyrosine (metyrosine) Adrenergic nerve terminals and adrenal medulla cytoplasm Blocks synthesis... 

In another successful case, Hexter and Westheimer (1971) were able to locate 5% of the total radioactivity in Tyr-146 after irradiation of [14C]diazoacetylchymotrypsin. The reaction is actually intermolecular, occurring in chymotrypsin dimers. Westheimer s group have determined the structure of several of the modified amino acids derived from the photolysis of proteolytic enzymes acylated with diazo reagents. Such data is not available for other photoaffinity reagents. Knowing that O-carboxy-methyl tyrosine was an expected insertion product Hexter and Westheimer (1971) were able to show that of the two Tyr residues in the chymotrypsin B chain only Tyr-146, the C-terminal residue, was modified. If the nature of the modified amino acid had not been known it would have been considerably more difficult to pin-point the site of photolabeling. 

A second fundamental insight arose from the same data. The similarities of the experimental akinesia produced by reserpine or a-methyl tyrosine to the bradykinesia of... 

Fig. 1. A. Chemical structure of key molecules involved in the key steps in intracerebral synthesis and metabolism of dopamine. The successive steps are regulated by the enzymes tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and dopamine-p-hydroxylase (DBH). B. Structure of key toxins and other drugs acting on dopamine neurones, including 6-hydroxydopamine (6-OHDA), a-methyl tyrosine, and amphetamine. For further details see Iversen and Iversen (1981) or Cooper et al. (1996).

Scyptolins A and B (Fig. 48) were isolated from axenic cultures of the terrestrial cyanobacterium Scytonema hofmanni PCC7110 by Matem et al. in 2001.They have the uncommon amino acid residue 3 -chloro-jV-methyl tyrosine and unique side chains. Both scyrtolin A and B exhibit selective inhibition of porcine pancreatic elastase in vitro with an IC50 of 3.1pg/ml l... 

Interesting central anti-amphetamine effects are described for tyros ie hydroxylase inhibitors such as a-methyl-tyrosine. Since norepinephrine depletors do not antagonize amphetamine and tyrosine hydroxylase inhibitors have little direct sedative effect, it is suggested that small but critical levels of norepinephrine at receptors are necessary for amphetamine to exert both its stimulant and anorexigenic effects. Whether this applies to other anorectic drugs remains to be determined. 

The iodonium salt shown with N-protected O-methyl tyrosine (sodium salt) in dimethytformamide at 90-95X gave the diaryl ether in 51% yield without racemisation, under these preferred milder conditions rather than by the Ullmann reaction (ref.67). 

Metyrosine is oc-methyl tyrosine, which competes with tyrosine for sites on tyrosine hydroxylase—the enzyme responsible for the rate-limiting step in catecholamine biosynthesis. Thus, it decreases catecholamine biosynthesis, resulting in a decrease in circulating levels of catecholamines. Metyrosine is a tyrosine hydroxylase inhibitor. 

From various reactions and instrumental analysis, structural relationships and the structures of RA-I (147) - RA-VIII (154) were determined as illustrated in Fig. 16. RA-VI (152) was elucidated as the configurational isomer of RA-III (149) at the moiety of D-O-methyl-tyrosine RA-VIII (154) has L-threonine instead of the L-serine in RA-III molecule. However, it was observed that RA-VII and RA-V were the main components in these oligopeptides. 

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