A-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). 

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. ... 

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. 

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).

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. 

A notable improvement in clinical condition has been obtained with a-methyl-tyrosine in patients suffering from phaeochromocytoma, a disease in which the s3onptomatology is directly related to the catecholamine production rate. On the other hand, the results achieved in patients with essential hypertension have been disappointing [71]. The 50-70% inhibition of catecholamine synthesis observed was apparently not sufficient in these patients to produce a fall in blood pressure. Sedation, anxiety, diarrhoea, and drug crystalluria were some of the side effects noticed with a-methyltyrosine. 

W-Methyl-i-tyrosine a-Methyl-/ /.-tyrosine, methyl ester, hydrochloride... 

Figure 2. Plasma corticosterone concentrations before and 15 minutes following stress (ether 1 min) in uninjected rats or animals that had received six hours earlier an intraperitoneal injection of a saline suspension of 1-tyrosine or a-methyl tyrosine in a dose of 200 mg/Kg. Number of animals given in parentheses.

Figure l-. Plasma ACTH concentrations before and 2.5 minutes after stress (ether 1 min. or ether 1 min. and sham unilateral adrenalectomy) in rats 2k hours after the removal of their adrenal glands and six hours after an intraperitoneal injection of 200 mg/Kg. body weight 1-tyrosine or 2, 20, or 200 mg/Kg. of a-methyl tyrosine. 

Figure 5 Comparison of the percent inhibition of the stress-induced secretion of ACTH and whole brain epinephrine/ norepinephrine content in intact, sham adrenalectomized, and 2k hour adrenalectomized rats given six hours earlier an intraperito-neal injection of different doses of a-methyl tyrosine.

Hydroxy-a-methyl-/.- tyrosine Methyidopa C10H13NO4 555-30-6 211.215 cry(MeOH) 300 dec ... 

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