Norepinephrine, from dopamine

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

Three amines—dopamine, norepinephrine, and epinephrine—are synthesized from tyrosine in the chromaffin cells of the adrenal medulla. The major product of the adrenal medulla is epinephrine. This compound constimtes about 80% of the catecholamines in the medulla, and it is not made in extramedullary tissue. In contrast, most of the norepinephrine present in organs innervated by sympathetic nerves is made in situ (about 80% of the total), and most of the rest is made in other nerve endings and reaches the target sites via the circu-... 

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. 

The chemical structure of histamine has similarities to the structures of other biogenic amines, but important differences also exist. Chemically, histamine is 2-(4-imidazolyl)ethylamine (Fig. 14-1). The ethylamine backbone is a common feature of many of the amine transmitters (e.g. dopamine, norepinephrine and serotonin). However, the imidazole nucleus, absent from other known transmitters, endows histamine with several distinct chemical properties. Among these is prototypic tautomerism, a property that permits it to exist in two different chemical forms (Fig. 14-1). The tautomeric properties of histamine are thought to be critical in the... 

In the brain, methamphetamine causes massive amounts of the neurotransmitters dopamine, norepinephrine, and serotonin to be released from neurons in the brain, particularly in the limbic system and frontal cortex. Scientists believe the increased dopamine release in these brain regions is responsible for methamphetamine s ability to keep people awake, alert, energetic, active, and possibly addicted. Methamphetamine acts on a variety of brain regions to produce a number of different effects (Table 2.1). 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

Lobeline also increases basal release of norepinephrine, but norepinephrine release may be reduced at higher lobeline concentrations (Rao et al. 1997). Unlike acetylcholine, lobeline does not reduce the release of dopamine or norepinephrine by NMDA receptors, but it does block nicotine-induced release of norepinephrine from the locus coeruleus (Gallardo and Leslie 1998). Lobeline also evokes release of serotonin, which is mediated by uptake transporters and unaffected by mecamylamine (Lendvai et al. 1996). 

Tyrosine (Tyr or Y) (4-hydroxyphenylalanine ((5)-2-amino-3-(4-hydroxyphenyl)-propanoic acid)) is a polar, neutral, aromatic amino acid with the formula H00CCH(NH2)CH2C6H50H and is the precursor of thyroxin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the pigment melanin. Being the precursor amino acid for the thyroid gland hormone thyroxin, a defect in this may result in hypothyroidism. Tyr is extremely soluble in water, a property that has proven useful in isolating this amino acid from protein hydrolysates. The occurrence of tyrosine- 0-sulfate as a constituent of human urine and fibrinogen has been reported. ... 

Stimulating Neurotransmitter Release. Psychostimulants, such as methylphe-nidate (Ritalin), can directly trigger the release of certain neurotransmitters (e.g., dopamine and norepinephrine) from the neuron s axon terminal. 

Histamine, serotonin, melatonin, and the catecholamines dopa, dopamine, norepinephrine, and epinephrine are known as "biogenic amines."They are produced from amino acids by decarboxylation and usually act not only as hormones, but also as neurotransmitters. 

Dextroamphetamine is a powerful stimulant of the nervous system that manifests its effects by releasing dopamine and norepinephrine from presynaptic nerve endings, thus stimulating central dopaminergic and noradrenergic receptors. In certain doses it strengthens the excitatory process in the CNS, reduces fatigue, elevates mood and the capacity to work, reduces the need for sleep, and decreases appetite. 

Hypotension Hypotension (postural) occurs regularly in about 50% of patients while they are supine, manifested by dizziness, light-headedness, vertigo, or faintness. Tolerance occurs unpredictably but may be present after several days. Hypotension with supine systolic pressure above 75 mm Hg need not be treated unless symptomatic. If supine systolic pressure falls below 75 mm Hg, infuse dopamine or norepinephrine to increase blood pressure use dilute solution and monitor blood pressure closely because pressor effects are enhanced by bretylium. Perform volume expansion with blood or plasma and correct dehydration where appropriate. Transient hypertension and increased frequency of arrhythmias Transient hypertension and increased frequency of arrhythmias may occur due to initial release of norepinephrine from adrenergic postganglionic nerve terminals. 

Dopamine is a unique adrenomimetic drug in that it exerts its cardiovascular actions by (1) releasing norepinephrine from adrenergic neurons, (2) interacting with a-and (3i-adrenoceptors, and (3) interacting with spe-cihc dopamine receptors. 

MAO A and B differ in primary structure and in substrate specificity [5,7]. The two isozymes, located on the mitochondrial outer membranes, have 70% homology in peptide sequence and share common mechanistic details. It is now recognized that these are different proteins encoded by different genes, but probably derived from a common ancestral gene. Crystal structures for both MAO A and B complexes with inhibitors have recently been reported [8]. Serotonin is selectively oxidized by MAO A, whereas benzylamine and 2-phenylethylamine are selective substrates for MAO B. Dopamine, norepinephrine, epinephrine, trypt-amine, and tyramine are oxidized by both MAO A and B in most species [9]. In addition, MAO A is more sensitive to inhibition by clorgyline (1), whereas MAO B is inhibited by low concentrations of L-deprenyl ((f )-( )-deprenyl) (2) [5,6cj. Development of inhibitors that are selective for each isozyme has been an extremely active area of medicinal chemistry [8]. 

Cyclization of the acid chloride by means of aluminum chloride gives tetralone (19-2). This is then converted to its A -methylimine (19-3) by means of methylamine and titanium tetrachloride. That intermediate is next reduced with sodium boro-hydride to give a mixture of cis and trans aminotetralins (19-4). The tmns isomer tametraline (19-5) is separated by fractional crystallization of the hydrochloride salt [20]. Detailed pharmacological investigations showed that this compound owes its antidepressant action to the inhibition of reuptake of dopamine and norepinephrine from the synaptic cleft. 

Other important nitrogen-containing compounds made from amino acids include the catecholamines (dopamine, norepinephrine, and epinephrine), which are synthesized from tyrosine creatine, which is synthesized from arginine and glycine histamine, which is synthesized from histidine and serotonin, which is synthesized from tryptophan. 

FIGURE 7—41. Adrenergic combo 2 Bupropion can be combined with a stimulant such as d-amphetamine or methylphenidate. The stimulant will add a double dopamine boost to bupropion, which boosts dopamine in its own right. A single boost of norepinephrine from bupropion also is present. 

Glutamate removal. Glutamate s actions ate stopped not by enzymatic breakdown, as in other neurotransmitter systems, but by removal by two transport pumps. The first of these pumps is a presynaptic glutamate transporter, which works as do all the other neurotransmitter transporters already discussed for monoamine neurotransmitter systems such as dopamine, norepinephrine, and serotonin. The second transport pump, located on nearby glia, removes glutamate from the synapse and terminates its actions there. Glutamate removal is summarized in Figure 10—22. 

FIGURE 12—5. Here, /-amphetamine is releasing norepinephrine from presynaptic noradrenergic neurons. It also does this from dopamine neurons, just as shown for (/-amphetamine in Figure 12—3. When /-amphetamine binds to ther-presynaptic norepinephrine transporter on the norepinephrine presynaptic nerve terminal, it not only blocks norepinephrine reuptake but actually causes norepinephrine release. Thus, /-amphetamine releases both norepinephrine and dopamine, whereas (/-amphetamine is selective for dopamine. Since norepinephrine and dopamine can have different if related cognitive functions in different patients, then d- and /-amphetamine can have different cognitive effects as well. 

TLC separation of DNS-amines is usually made on layers of silica gel with solvents covering a range of polarity, e.g., chloroform, ethyl acetate, diisopropyl ether and methanol. Seiler and Wiechmann [97] developed 30 solvent systems for the separation of DNS derivatives of over 100 biogenic amines on TLC plates of silica gel. The selective reaction of DNS-C1 with the amino group of catecholamines has been examined [98]. The drugs dopamine, norepinephrine and epinephrine are adsorbed on alumina which protects their hydroxyl groups from dansylation. The N-dansylated compounds are separated with benzene-dioxane-acetic acid (90 25 4) on layers of silica gel. 

How precisely does cocaine achieve these effects in the brain As described in Chapter i, once a neurotransmitter is released from its neuronal terminal, its actions within the synapse are ended principally by reuptake into the presynaptic terminal. Cocaine primarily blocks the reuptake of dopamine but also acts similarly on norepinephrine and serotonin reuptake. If your neuronal terminals can be seen as acting like little vacuum cleaners, then cocaine essentially clogs the vacuum nozzle. As a consequence of this blockade, the concentrations of dopamine, norepinephrine, and serotonin within the synaptic cleft between two neurons increases dramatically. Withinmillions of synapses in the brain, these neurotransmitters are now free to continue to stimulate their receptors over and over, again and again. There are neuronal terminals for dopamine, norepinephrine, and serotonin scattered throughout the entire brain, and thus the consequences of cocaine on brain function are also widespread. 

Recent studies suggest that the brain may contain its own family of valium-like compounds, the P-carbolines. Some of these antagonize GABA function and others enhance it, but all may share a similar ability to inhibit the destruction of the neurotransmitters dopamine, norepinephrine, and serotonin taken together, these effects would tend to produce a mild, relaxed euphoria. The balance of action of these endogenous antianxiety compounds is determined by the genes we inherit from our parents, which control the carbolines produced and probably... 

The catecholamine-synthesizing enzymes are not only able to synthesize dopamine and norepinephrine from a physiologically occurring substrate such as levodopa, but also from exogenous substrates such as a-methyldopa, which is converted to a-methyldopamine and in turn to a-methylnorepinephrine. a-methyldopamine and a-methylnorepinephrine are called false transmitters and, in general (except for a-methylnorepinephrine), are weaker agonists, a-methyldopa is used in the management of hypertension. 

The amphetamine class of stimulants are potent, indirect-acting agents that cause a release of the neurotransmitters dopamine and norepinephrine from storage areas in the CNS. The mildest CNS stimulant is phenethylamine (PEA), a component of cheese and chocolate, while cocaine is considered a potent CNS stimulant. 

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