ALPHA-METHYL-L-P-TYROSINE

Absorption

Well absorbed from the gastrointestinal tract.

Toxicity

Signs of metyrosine overdosage include those central nervous system effects observed in some patients even at low dosages. At doses exceeding 2000 mg/day, some degree of sedation or feeling of fatigue may persist. Doses of 2000-4000 mg/day can result in anxiety or agitated depression, neuromuscular effects (including fine tremor of the hands, gross tremor of the trunk, tightening of the jaw with trismus), diarrhea, and decreased salivation with dry mouth. The acute toxicity of metyrosine was 442 mg/kg and 752 mg/kg in the female mouse and rat respectively.

Chemical properties

White Solid

Originator

Demser,MSD,US,1979

The Uses of ALPHA-METHYL-L-P-TYROSINE

α-Methyl-L-tyrosine is used to determine whether Fe²/ methamphetamine (METH) -induced cell death is dependent on cytosolic dopamine and iron mediated oxidative stress.

The Uses of ALPHA-METHYL-L-P-TYROSINE

A tyrosine hydroxylase inhibitor. An antihypertensive in pheochromocytoma

The Uses of ALPHA-METHYL-L-P-TYROSINE

Metyrosine is the α-methyl derivative of tyrosine. It competitively inhibits tyrosine hydroxylase action, thus reducing the formation of epinephrine and norepinephrine. It is used for treating patients with pheochromocytoma, in cases where a rise in the level of catecholamines is observed.

Indications

For use in the treatment of patients with pheochromocytoma, for preoperative preparation of patients for surgery, management of patients when surgery is contraindicated, and chronic treatment of patients with malignant pheochromocytoma.

What are the applications of Application

α-Methyl-L-p-tyrosine is a TH (tyrosine hydroxylase) inhibitor

Background

An inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is used to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma. (Martindale, The Extra Pharmacopoeia, 30th ed)

Definition

ChEBI: An L-tyrosine derivative that consists of L-tyrosine bering an additional methyl substituent at position 2. An inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is us d to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma.

Manufacturing Process

50 g of α-methyl-N-dichloroacetyl-p-nitrophenylalanine was dissolved in 500 ml methanol, 300 mg of platinum oxide were added and the mixture reduced at 41 pounds of pressure; within an hour 14.5 pounds were used up (theory 12.4 pounds). After filtration of the catalyst, the red clear filtrate was concentrated in vacuo and the residual syrup flushed several times with ether. The crystalline residue thus obtained, after air drying, weighed 45.3 g (99.5%), MP unsharp at about 104°C to 108°C with decomposition. After two precipitations with ether from an alcoholic solution, the somewhat hygroscopic amine was dried over sulfuric acid for analysis.
10 g of the amine prepared above was dissolved in 5 ml of 50% sulfuric acid at room temperature; the viscous solution was then cooled in ice and a solution of sodium nitrite (2.4 g) in 10 ml water gradually added with agitation. A flocculent precipitate formed. After all the nitrite had been added, the mixture was aged in ice for an hour, after which it was allowed to warm up to room temperature. Nitrogen came off and the precipitate changed to a sticky oil. After heating on the steam bath until evolution of nitrogen ceased, the oil was extracted with ethyl acetate. After removal of the solvent in vacuo, 9.4 g of colored solid residue was obtained, which was refluxed with 150 ml hydrochloric acid (1:1) for 17 hours. The resulting dark solution; after Norite treatment and extraction with ethyl acetate, was concentrated in vacuo to dryness and the tan colored residue (7.4 g) sweetened with ethanol. Dissolution of the residue in minimum amount of ethanol and neutralization with diethylamine of the clarified solution, precipitated the α-methyl tyrosine, which was filtered, washed with ethanol (until free of chlorides) and ether. The crude amino acid melted at 309°C with decomposition. For further purification, it was dissolved in 250 ml of a saturated sulfur dioxide-water solution, and the solution, after Noriting, concentrated to about 80 ml, the tan colored solid filtered washed with ethanol and ether. Obtained 1.5 g of α-methyl tyrosine, MP 320°C dec.

brand name

Demser (Merck).

Therapeutic Function

Tyrosine hydroxylase inhibitor

General Description

Metyrosine (α-Methyl-L-tyrosine, Demser). Althoughinhibition of any of the three enzymes involved in CA biosynthesisshould decrease CAs, inhibitors of the first andthe rate-limiting enzyme TH would be the most effective.As such, metyrosine is a much more effective competitiveinhibitor of E and NE production than agents that inhibitany of the other enzymes involved in CA biosynthesis. Itis often possible to “fool” the enzymes into accepting astructurally similar and unnatural substrate such as metyrosine.Metyrosine differs structurally from tyrosine onlyin the presence of an α-methyl group . It is oneexample of a CA-biosynthesis inhibitor in clinical use.Although metyrosine is used as a racemic mixture, it is the (-)isomer that possesses the inhibitory activity.Metyrosine, which is given orally in dosages ranging from 1 to 4 g/day, is used principally for the preoperative managementof pheochromocytoma, chromaffin cell tumorsthat produce large amounts of NE and E. Although theseadrenal medullary tumors are often benign, patients frequentlysuffer hypertensive episodes. Metyrosine reducesthe frequency and severity of these episodes by significantlylowering CA production (35%–80%). The drug ispolar (log P＝0.73) and excreted mainly unchanged in theurine. Because of its limited solubility in water caused byintramolecular bonding of the zwitterions, crystalluria is apotential serious side effect. It can be minimized by maintaininga daily urine volume of more than 2 L. Inhibitors ofCA synthesis have limited clinical utility because suchagents nonspecifically inhibit the formation of all CAs andresult in many side effects. Sedation is the most commonside effect of this drug.
A similar example is the use of α-methyl-m-tyrosine inthe treatment of shock. It differs structurally from metyrosineonly in the presence of m-OH instead of p-OH inmetyrosine. This unnatural amino acid is accepted by the enzymesof the biosynthetic pathway and converted tometaraminol (an α-agonist).

Biochem/physiol Actions

α-Methyl-L-tyrosine (L-AMPT) acts as a competitive inhibitor of tyrosine hydroxylase and inhibits the conversion of tyrosine to L-DOPA and eventually lowers dopamine synthesis in cytosol. AMPT at low concentrations can be used as a potent therapeutic for refractory dystonia or dyskinesia. It also helps in decreasing catecholamine concentration in pheochromocytoma patients.

Pharmacokinetics

In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of metyrosine per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after metyrosine is discontinued. Most patients with pheochromocytoma treated with metyrosine experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with metyrosine; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.

Synthesis

Metyrosine, (?)|á-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 hydantoin (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 |á-methyl-D,L-tyrosine, from which the desired L-isomer is isolated (12.3.11) [83¨C86].

Metabolism

Little biotransformation, with catechol metabolites accounting for less than 1% of the administered dose.