DIOXYPHENYLALANINE, dihydroxyphenylalanin (dihydroxyphenylalanin, in abbreviated form DOFA, DOPA) — beta (3,4 dioxyphenyl) - alpha lactamic acid; intermediate compound in the course of education in an organism of animals and the person of biologically important connections — adrenaline and melanin, is applied as medicine. Constitutional formula of D.:
Belongs along with tyrosine (see) and phenylalanine (see) to aromatic to amino acids (see), however is not a part of proteins. Existence of small amounts of free D. in fabrics of an animal organism is explained by its education from tyrosine by oxidation of the last enzyme about-difenoloksidazoy (a tyrosinase, KF 220.127.116.11). Also specific hydrolase (KF 18.104.22.168) is found in some tissues of animals, the cut is a cofactor tetrahydropteridine, D. catalyzing education from tyrosine; the mechanism of this reaction is similar hydroxylations) phenylalanine to tyrosine. D.'s synthesis from pyruvate, ammonia and pyrocatechin in reaction, by the catalyzed beta tyrosinase (tyrosine-phenol-lyase) is found in some microorganisms. This enzyme in the presence of pyridoxal phosphate catalyzes also formation of pyruvate and ammonia from many beta replaced amino acids, including from D., tyrosine and DL-serina. Enzymic oxidation of D. in a human body and animals with the participation of enzyme about-difenoloksidazy leads to formation of colored compounds of quinoid type which further spontaneous transformations lead to formation of brown pigments — melanin (see). au-Difenoloksidaza is in the cells forming pigments; are especially rich with this enzyme of a cell of the pigmented sites of skin and pigmental tumors (melanomas). In leather of albinos and in not pigmented sites of skin about-difenoloksidaza it is not found. In process decarboxylations (see) D., proceeding at action of the DOFA-decarboxylase (KF22.214.171.124), dopamine (oxytyramine), being the direct predecessor of noradrenaline and adrenaline at the person and animals is formed (see the scheme).
The oxidation of dopamine to noradrenaline catalyzed dopamine - beta monooxygenase (KF 126.96.36.199), happens in the presence of ascorbic to - you, a fumarat and molecular oxygen. Process of formation of adrenaline of noradrenaline proceeds with the participation of the enzyme of fenilaminoetanol-N-methyltransferase catalyzing methylation of a number of derivatives of a fenilaminoetanol, including noradrenaline. The methyl S-adenozilmetionina group takes part in this reaction.
It is established that at patients parkinsonism (see) in subcrustal nodes of a brain the content of biogenic amines — noradrenaline, serotonin and especially dopamine is reduced.
The origin of parkinsonism is connected with damage of nigrostriatny dofaminergichesky neurons and weakening of influence of dopamine on activity of cells of a kernel having a tail. As dopamine does not get through a blood-brain barrier, is applied to increase in its concentration in a brain. Under the influence of the DOFA-decarboxylase of a brain it easily turns into dopamine.
See also DOFA-reaction .
Dioksifenilalanin as drug
Drug D., is more faithful than it L-DOFA laevoisomer (a synonym levodopa, larodopa, Dopa-flexd), is an effective remedy for treatment of parkinsonism. Drug represents white crystal powder, water soluble only at alkaline pH values. Therapeutic action of L-DOFA, apparently, is caused by activation of striatny dopamine receptors; perhaps, it is connected with D.'s transformation into the specific metilirovanny connection possessing antiparkinsonichesky action. Quickly facilitates a condition of patients with parkinsonism. Especially well such symptoms of a disease as rigidity and an akineziya are eliminated; also the tremor decreases. Cases of parkinsonism, resistant to L-DOFA meet, however.
Drug is appointed inside along with meal. Treatment begin with small doses (0,1 — 0,25 g 4 times a day), and then each 5 — 6 days a dose increase by 0,1 — 0,2 g to considerable a wedge, improvements or emergence of side reactions (usually not less than 4 g and no more than 8 g a day). Having defined thus individually tolerable dose, lower it by 0,5 — 1,0 g and, using an optimum therapeutic dose, conduct treatment of 6 — 12 months and longer.
Co-administration with L-DOFA of inhibitors of a peripheral DOFA-decarboxylase allows to reduce amount of the administered drug (sometimes by 10 times) at the expense of the prevention its decarboxylation in a liver and intestines. It reduces expressiveness of by-effects. The same goal is achieved a combination of L-DOFA with other antiparkinsonichesky substances (Cyclodolum, amantadiny).
Complications at treatment divide into 3 groups: gastrointestinal (loss of appetite, nausea, vomiting), cardiovascular (hypotension, cardiac arrhythmias) and neuromental (psychotic states, depressions). In the first months of therapy nausea and vomiting is most often observed, are more typical for late terms dyskinesia. Use of L-DOFA is not recommended to be combined with a pyridoxine which weakens D.'s action, with the MAO nek-ry inhibitors and Phenaminum increasing toxicity of drug and also with antihypertensives and nek-ry neuroleptics (aminazine, Reserpinum), L-DOFA is contraindicated to patients at whom it is available signs of endocrine, renal, liver or cardiovascular failure, at glaucoma, psychoses and heavy psychoneuroses.
Form of release: tablets on 500 mg.
Bibliography: Arushanyan E. B. A role of dopamine in physiology and pathology basal gangliyev, Zhurn, a neuropath, and psikhiat., t. 72, No. 4, page 595, 1972; Braunstein A. E. Biochemistry of amino-acid exchange, page 21, etc., M., 1949, bibliogr.; With arlsson A. Biochemical and pharmacological aspects of parkinsonism, Acta neurol. scand., v. 48, Suppl. 51, p. 11, 1972, bibliogr.; E n e i H. o. Enzymatic preparation of L-tyrosine and 3,4-dihydro xyphenyl-L-alanine, Biochem. biophys. Res. Commun., v. 43, p. 1345, 1971; Klawans H., Ilani M. M. a. Shenker D. Theoretical implications of the use of L-DOPA in parkinsonism, Acta neurol. scand., v. 46, p. 409, 1970, bibliogr.; L-DOPA and parkinsonism, ed. by A. Barbeau a. F. H. McDowell, Philadelphia, 1970; MeisterA. Biochemistry of the amino acids, v. 1—2, N. Y. — L., 1965, bibliogr.
E. V. Goryachenkova; E. B. Arushanyan (pharm.).