Brain norepinephrine biosynthesis

Introduction of chlorine or bromine into the 3- and/or 4- positions of the side chain yields more potent compounds in terms of hypotension in rats and dopamine p- hydroxylase inhibition (31. 32). The analog YP-279 (XXXV) is also hypotensive in rats but is said not to affect brain norepinephrine biosynthesis unlike fusaric acid or dibromofusaric acid (33-35). Fusaric acid amide (bupicomide, Sch 10595, XXXVI) is clinically effective at 300 to 1800 mg per day and is said to have hemodynamic effects similar to hydralazine (36. 37). The amide is... 

Levodopa (L-dopa) is a natural intermediate in the biosynthesis of catecholamines in the brain and peripheral adrenergic nerve terminals. In the biologic sequence of events it is converted to dopamine, which in turn serves as a substrate of the neurotransmitter norepinephrine. Levodopa is used successfully in the treatment of Parkinson s syndrome, a disease characterized by dopamine deficiency. When levodopa is administered to an individual with this syndrome, the symptoms of Parkinson s disease are ameliorated, presumably because the drug is converted to dopamine and thereby counteracts the deficiency. Individuals treated with levodopa, especially older men, have been observed to experience a sexual rejuvenation. This effect has led to the belief that levodopa stimulates sexual powers. Consequently, studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and the incidence of penile erections. Overall, however, these effects are short lived and do not reflect continued satisfactory sexual function and potency. Thus, levodopa is not a true aphrodisiac. The increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved well-being and partial recovery of normal sexual functions that were impaired by Parkinson s disease. 

Catecholamines are endogenous compounds and are synthesized in the brain, the adrenal medulla, and by some sympathetic nerve fibers. The biosynthesis of catecholamines begins with the hydroxylation of tyrosine by tyrosine hydroxylase to form L-dopa, which is decarboxylated by aromatic amino acid decarboxylase to form dopamine. Norepinephrine... 

Dopamine -hydroxylase (EC 1.14.17.1) is a glycoprotein which hydroxylates dopamine to norepinephrine during the biosynthesis of catecholamines. The enzyme occurs in the synaptic vesicles of noradrenergic and adrenergic brain... 

This interest in the nature of chemical transmission in the central nervous system continues to bear fruit. For example, studies on nerve terminals of postganglionic adrenergic fibers (6) and on the adrenal medulla had, over a period of many years, provided a fairly clear picture of the biosynthesis, release, reuptake, and destruction of the adrenergic transmitter norepinephrine. Other studies had shown that in patients with classical Parkinson s disease parts of the brain—the substantia nigra and corpus striatum—contained less dopamine than did normal brains (7). Dopamine is one of the intermediates in the biosynthesis of norepinephrine from phenylalanine. 

The accumulation of phenylalanine and its metabolites may interfere with the metabolism of other amino acids. Stein and Moore, and later Knox, showed that in phenylketonuric patients the amount of other amino acids in the plasma is decreased while phenylalanine accumulates. This interaction between the amino acids metabolism acquires particular significance in view of the mode of amino acid uptake in the brain. The investigators demonstrated that phenylalanine inhibits tyrosine uptake in the brain. Thus, in the presence of large amounts of phenylalanine, protein synthesis in the brain might be inhibited. Furthermore, because of the absence of tyrosine, the biosynthesis of well-known neuroregulators derived from tyrosine, such as norepinephrine and 3,4-dihydroxyphenylethyl-amine, could also be reduced in the brain. 

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