Catecholamines precursors

Brand Name(s) Atamet, Parcopa, Sinemet, Sinemet CR Cfiemical Class Catecholamine precursor... 

Dopa Antidepressant effect in some cases Prevents sedation after reserpine Greater supply of catecholamine precursors... 

Neurotensin. Neurotensia [39379-15-2] (NT),j )-Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Try-Ile-Leu-OH, is a tridecapeptide that is cleaved from the ribosomaHy synthesized precursor, proneurotensia. NT is distributed through the peripheral and central nervous systems as well as ia certain other cell types (3,67). NT is colocalized with catecholamines ia some neurons. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Together with dopamine, adrenaline and noradrenaline belong to the endogenous catecholamines that are synthesized from the precursor amino acid tyrosine (Fig. 1). In the first biosynthetic step, tyrosine hydroxylase generates l-DOPA which is further converted to dopamine by the aromatic L-amino acid decarboxylase ( Dopa decarboxylase). Dopamine is transported from the cytosol into synaptic vesicles by a vesicular monoamine transporter. In sympathetic nerves, vesicular dopamine (3-hydroxylase generates the neurotransmitter noradrenaline. In chromaffin cells of the adrenal medulla, approximately 80% of the noradrenaline is further converted into adrenaline by the enzyme phenylethanolamine-A-methyltransferase. 

Some hormones are synthesized in final form and secreted immediately. Included in this class are the hormones derived from cholesterol. Others such as the catecholamines are synthesized in final form and stored in the producing cells. Others are synthesized from precursor molecules in the producing cell, then are processed and secreted upon a physiologic cue (insuhn). Finally, stiU others are converted to active forms from precursor molecules in the periphery (T3 and DHT). All of these examples are discussed in more detail below. 

Tyrosine is the immediate precursor of catecholamines, and tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis. Tyrosine hydroxylase is found in both soluble and particle-bound forms only in tissues that synthesize catecholamines it functions as an oxidoreductase, with tetrahydropteridine as a cofactor, to convert L-tyrosine to L-dihydroxyphenylalanine (L-dopa). 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

The turnover rate of a transmitter can be calculated from measurement of either the rate at which it is synthesised or the rate at which it is lost from the endogenous store. Transmitter synthesis can be monitored by administering [ H]- or [ " C]-labelled precursors in vivo these are eventually taken up by neurons and converted into radiolabelled product (the transmitter). The rate of accumulation of the radiolabelled transmitter can be used to estimate its synthesis rate. Obviously, the choice of precursor is determined by the rate-limiting step in the synthetic pathway for instance, when measuring catecholamine turnover, tyrosine must be used instead of /-DOPA which bypasses the rate-limiting enzyme, tyrosine hydroxylase. 

These are four monoamines synthesized and seereted within many mammalian tissues, ineluding various regions in the brain, sympathetic nervous system, enlero-chromafhn cells of the digestive tract, and adrenal mednlla. These biogenic amines (indoleamine and catecholamines — dopamine, norepinephrine, and epinephrine) are synthesized within the cell from their precursor amino acids and have been associated with many physiological and behavioral functions in animals and humans. 

The catecholamines dopamine, norepinephrine and epinephrine are neurotransmitters and/or hormones in the periphery and in the CNS. Norepinephrine is a neurotransmitter in the brain as well as in postganglionic, sympathetic neurons. Dopamine, the precursor of norepinephrine, has biological activity in the periphery, most particularly in the kidney, and serves as a neurotransmitter in several important pathways in the CNS. Epinephrine, formed by the N-methylation of norepinephrine, is a hormone released from the adrenal gland, and it stimulates catecholamine receptors in a variety of organs. Small amounts of epinephrine are also found in the CNS, particularly in the brainstem. 

Two amino acids, tyrosine and arginine are of particular importance as precursors of signalling molecules. As outlined in Figure 4.3, tyrosine is the amino acid precursor of thyroid hormones tri-iodothyronine (T3) and tetra-iodothyronine (T4) and also of catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). 

Tyrosine is also the metabolic precursor to the neurotransmitter dopamine and the catecholamine hormones norepinephrine (noradrenaline) and epinephrine (adrenaline), as well as to the alkaloids in opium, including morphine. 

The catecholamines are formed from the dietary amino acid precursors phenylalanine and tyrosine, as illustrated in Figure 2.16. 

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. 

The preparation of fluorinated catechols and phenols and particularly fluori-nated derivatives of the catecholamines and aminoacids has led to the search for methods which do not induce racemization of chiral precursors. Benzaldehydes and alkoxybenzaldehydes are considered as latent phenols and catechols respec-... 

Several amino acids are broken down by de-carbo qflation. This reaction gives rise to what are known as biogenic amines, which have various functions. Some of them are components of biomolecules, such as ethanolamine in phospholipids (see p. 50). Cysteamine and T-alanine are components of coenzyme A (see p.l2) and of pantetheine (see pp. 108, 168). Other amines function as signaling substances. An important neurotransmitter derived from glutamate is y-aminobutyrate (GABA, see p.356). The transmitter dopamine is also a precursor for the catecholamines epinephrine and norepinephrine (see p.352). The biogenic amine serotonin, a substance that has many effects, is synthesized from tryptophan via the intermediate 5-hydroxytryptophan. 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

Dopamine is a naturally occurring catecholamine it is the immediate biochemical precursor of the norepinephrine found in adrenergic neurons and the adrenal medulla. It is also a neurotransmitter in the CNS, where it is released from dopaminergic neurons to act on spe-cihc dopamine receptors (see Chapter 31). 

The storage and release of DA can be modified irreversibly by reserpine (3.1), just as in vesicles containing other catecholamines and serotonin. Dopamine release can be blocked specifically by y-hydroxybutyrate (4.78) or its precursor, butyrolactone, which can cross the blood-brain barrier. High doses of amphetamines do deplete the storage vesicles, but this is not their principal mode of action. Apparently, amantadine (4.79), an antiviral drug that is likewise beneficial in parkinsonism (and also perhaps to relieve fatigue in multiple sclerosis), may also act by releasing DA. 

Dopamine is an endogenous catecholamine and an immediate precursor of adrenaline and noradrenaline. At low doses it stimulates vascular DAI dopaminergic receptors, especially those in renal, mesenteric and coronary vessels. As the dose increases it progressively stimulates 31 and al adrenoceptors. Thus, depending on the dose it may act as a renal vasodilator, a myocardial inotrope, or a peripheral vasoconstrictor. Dopamine also causes release of noradrenaline from autonomic nerve endings (DA2 receptors). 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

---