Synthesis and Significance of Biological Substances: 5-HT, Melatonin, Dopamine, Noradrenaline, Adrenaline : Pharmaceutical Guidelines -->

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Synthesis and Significance of Biological Substances: 5-HT, Melatonin, Dopamine, Noradrenaline, Adrenaline

The enterochromaffin cells and serotonergic neurons produce serotonin from L-tryptophan, whereas platelets are dependent on the uptake of serotonin.

5-HT (5-hydroxytryptamine)

Synthesis and Significance

There are three main types of cells that store serotonin (5-hydroxytryptamine) -
  • Blood platelets
  • Neurons in the central nervous system of the brain and the intestinal myenteric plexus,
  • Mucosa of the gastrointestinal tract contains enterochromaffin cells
The enterochromaffin cells and serotonergic neurons produce serotonin from L-tryptophan, whereas platelets are dependent on the uptake of serotonin. Serotonin transporters support amine uptake in serotonergic neurons as well. A precursor of melatonin (N-acetyl-5-methoxytryptamine) is synthesized in the pineal gland by enzymatic synthesis of serotonin.

In the cytosol of brain cells, the enzyme L-tryptophan hydroxylase (TPH) is involved in the synthesis of serotonin through the conversion of L-tryptophan to 5-hydroxytryptophan. Serotonin synthesis in neurons is regulated by this enzyme in a similar fashion to that by the related enzyme L-tyrosine hydroxylase, which converts L-tyrosine to L-dihydroxyphenylalanine (L-DOPA). There are some TPH inhibitors (such as α-propyldopacetamide) that also inhibit tyrosine hydroxylase, whereas other inhibitors such as p-chlorophenyl alanine operate more selectively. While p-chloroamphetamine and fenfluramine can also inhibit TPH, they also regulate a number of other serotonergic neuronal processes (including those that cause neurotoxicity). In the future, it may be possible to develop drug inhibitors for specificities in targeting individual enzyme isoforms as a result of the discovery of two enzyme isoforms, TPH1 and TPH2.

After 5-hydroxytryptophan goes through decarboxylation in the cytosol by the L-aromatic amino acid decarboxylase, serotonin (and also norepinephrine or dopamine) follows. These drugs do not cross the blood brain barrier and get absorbed into the nervous system, so they are used clinically for preventing peripheral decarboxylation of L-DOPA after it has been administered as a precursor of central dopamine in Parkinson's patients.

The monoamine oxidase enzyme (MAO) that occurs as two cellular subtypes called MAO-A and MAO-B metabolizes serotonin primarily. Despite widespread occurrence in the brain and in peripheral tissues, both subtypes are distinct in their extent of presence in certain tissues and cell types, including variations related to species. There is also a difference in the substrate specificity and inhibitor sensitivity of the subtypes. Due to its high affinity for the substrate and lower Km value, MAO-A is more selective for the oxidation of serotonin than MAO-B. There is evidence that nonselective (e.g., phenelzine) and subtype selective (e.g., moclobemide) MAO inhibitors can be effective antidepressants by preventing serotonin synthesis in the CNS. An interesting finding was that immunohistochemical studies indicated neurons with serotonin contained only MAO-B. MAO-A and MAO-B crystal structures have provided insight into the molecular topography of each subtype that may influence drug access to their catalytic sites, which may explain the substrate specificities and inhibitor features of each subtype. AHA is readily metabolized by ALDH2, a mitochondrial enzyme, to form aldehyde dehydrogenase, which is converted to 5-hydroxyindole acetic acid, serotonin's most important metabolite. 5-hydroxyindole acetaldehyde can be converted to 5-hydroxytryptophol via aldehyde reductase, but this metabolic pathway is not normally considered significant.

Melatonin

Synthesis

Cells from plants produce higher levels of melatonin than those from animals, likely because mitochondria and chloroplasts are two sources of melatonin, respectively, whereas animal cells only produce one source. Melatonin is present in both plants and animals, so it is reasonable to ask what mechanisms both plants and animals use for modulating this indole-containing compound's biosynthesis. According to current research, animals and plants have fundamentally different mechanisms for controlling melatonin synthesis. Melatonin is considered the chemical expression of darkness in vertebrates (based on only pineal and blood levels); in plants, a cycle is less common, although it does exist in some species, with melatonin levels rarely changing considerably over the course of light and dark cycles. Therefore, in some plants melatonin is not synthesized in a regular rhythm, as it occurs in animal mitochondria. NAT and melatonin production are suppressed by light detection in vertebrates. Melatonin concentrations in plants are correlated with light intensity. Plants growing in habitats with high levels of light, such as Mediterranean or alpine habitats, usually produce more melatonin than the same or related species grown elsewhere. There is evidence that melatonin is enhanced by even short periods of darkness in some species, such as 1 hour of darkness in rice seedlings, indicating that ASMT expression is elevated in response to darkness. Furthermore, Oryza showed that light curbed heat-induced melatonin elevations. Vertebrates have differences in signal transduction pathways and regulatory mechanisms in addition to these exceptions. Plants lack norepinephrine and its receptors, which are critical to melatonin synthesis in mammals, which indicates the absence of this pathway during evolution.

It has been noted that in order for melatonin to be produced, four successive enzymes must be activated. Although ASMT may limit this level around the nocturnal melatonin maximum, it is usually thought that NAT is the rate-limiting enzyme in pineal melatonin synthesis in vertebrates. Melatonin production correlates well with NAT activity for plants under most circumstances. Melatonin levels are highest when ASMT expression is enhanced in rice seedlings, however. Animals are typically characterized by a close relationship between NAT and melatonin production. According to the taxa of animals studied, NAT may or may not be regulated in the pineal gland. NAT mRNA levels are stimulated up to two orders of magnitude in some species with NAT mRNA levels influenced primarily by the suprachiasmatic nucleus (SCN).

Significance

A human's pineal gland, located in the cerebrum's center, makes the hormone melatonin. It regulates numerous vital processes in the body. A major effect of this therapy is the restoration of the natural cycle of organism functions. During shift work, changing time zones (during intercontinental air travel) or insomnia, it has the ability to eliminate disruptions in our circadian rhythm. Sleep quality and mood are improved. Melatonin functions can delay aging processes by scavenging free radicals, stabilizing biological rhythms, or stimulating the immune system. With its proper supplementation, our bodies can live a long, healthy life, keeping them both physically and psychologically in good condition. Additionally, melatonin has beneficial health properties, such as the ability to prevent some illnesses (neoplastic diseases, cardiovascular system disease, and other physiological disorders). It contributes to the improvement of mood, decreases susceptibility to stress, and strengthens the immune system.

Dopamine

Synthesis

The amino acid tyrosine is synthesized into dopamine, which then travels to the brain via an active transport system. An enzyme, phenylalanine hydroxylase, produces tyrosine from phenylalanine in the liver. As a result, a series of reactions converts the tyrosine into dopamine at dopamine-containing neurons. Tyrosine hydroxylase adds a hydroxyl group to tyrosine at the meta position, which produces L-dopa in catecholaminergic neurons. High levels of catecholamines (end product inhibition) inhibit this rate-limiting step of catecholamine synthesis. In general, tyrosine levels do not readily influence catecholamine synthesis because tyrosine hydroxylase is normally saturated with substrate. The dopa decarboxylase in the cytoplasm converts L-dopa to dopamine as soon as it is formed. Several new studies indicate that this enzyme does not just decarboxylate L-dopa, but also other natural aromatic amino acids, including tryptophan, and is thus called aromatic amino acid decarboxylase.

Significance

Neurotransmitter dopamine plays a role in the brain. Nerve cells use it to send messages between each other, and your body produces it. Chemical messengers have that name because they carry messages between neurons. Dopamine contributes to the feeling of pleasure. We use it to think and plan, and it's part of the reason we are unique as humans. Striving, focusing, and finding something interesting rely on it.

Noradrenaline

Synthesis

In order to investigate the importance of nerve impulses for these processes, experiments have looked at changes in noradrenaline synthesis and utilization in a rat spinal cord segment.

Tolazoline (50 mg/kg), yohimbine (10 mg/kg), and piperoxan (60 mg/kg) accelerated the alpha-methyltyrosine-induced disappearance of noradrenaline in the spinal cord. This disappearance was decelerated when nerve impulses were not present caudal to a spinal cord lesion, in contrast with that occurring cranially, and it was not affected by the three alpha-adrenoreceptor blocking agents.

The alpha-adrenoreceptor stimulating agent clonidine (0.1 mg/kg) was effective in decreasing the nialamide-induced accumulation of normetanephrine in the whole brain. Clonidine was completely inhibited by yohimbine, but not by phenoxybenzamine, providing further evidence that clonidine and yohimbine are more potent inhibitors of noradrenaline release than phenoxybenzamine.

In contrast to yohimbine, piperoxan, and tolazoline which decelerate Dopa accumulation cranial to the spinal cord lesion, phenoxybenzamine and haloperidol (10 mg/kg) have no significant effect. A spinal cord lesion lacking nerve impulses caudal to it caused popa accumulation to behave differently than the one cranial to the lesion, and it did not respond to alpha - adrenoreceptor blocking agents or clonidine.

Nerve impulses are required for both the synthesis of and the use of noradrenaline normally, as well as the acceleration of these processes when alpha-adrenoreceptors are blocked. It has been suggested that nerve impulses may act to stimulate noradrenaline synthesis and utilization via alpha-adrenoreceptors located on nerve terminals, cell bodies, or both parts of the noradrenergic neuron. Unlike the synthesis of dopamine, noradrenaline synthesis is not regulated by nerve impulses but by receptor-mediated feedback mechanisms.

Significance

  • As a neurotransmitter, it helps the sympathetic postganglionic nerves communicate with the innervated organs. The release of noradrenaline by the postganglionic neuron is triggered when an action potential arrives at the nerve terminal. In the post junctional membrane of neuroeffector cells (smooth muscle, cardiac muscle, or glands), it diffuses across the cleft to receptor (adrenoceptor) sites specifically alpha adrenocpetors. The hormone noradrenaline is helpful in restoring a normal blood pressure in a chronic hypotensive state once a blood volume deficit has been corrected.
  • All vascular beds are affected by peripheral arteriolar vasoconstriction as noradrenaline's main therapeutic effect. There is a rise in mean arterial pressure due to both elevated systolic and diastolic blood pressure. noradrenaline has a half-life ranging from 30 seconds to 3 minutes. Inhibits mono-amino oxidase and β-blockers, digitalis glycosides, tricyclic antidepressants, cocaine, and oxytocin.
  • Some of the adverse reactions include anxiety, dizziness, pallor, tremors, insomnia, headaches, and palpitations.
  • Patients with atherosclerosis, mesenteric or peripheral thrombosis or other occlusive vascular diseases, metabolic acidosis, hypoxia or hyperthyroidism should use this medication with caution.

Adrenaline

Synthesis

The amine hormone epinephrine is synthesized in the brain. The adrenal medulla, a region of the adrenal gland located in the middle of the gland, produces and releases this hormone. Enzymes convert L-dopa into dopamine, which is then converted to norepinephrine through a multistage process. Norepinephrine (noradrenaline) synthesizes epinephrine, which then enters the bloodstream. Catecholamines are the catecholamines epinephrine and norepinephrine. Catecholamines are released as part of the body's response to stress, and approximately 80% of those are epinephrine.

Significance

  • A faster heartbeat pumps additional blood throughout the body, particularly to the muscles, to prepare for movement.
  • Increasing blood pressure is caused by constriction of the blood vessels.
  • During exhalation, the bronchioles dilate to allow more oxygen into the bloodstream.
  • It is the liver that converts glycogen (the stored form of glucose) to glucose and releases it.
  • Energy is derived from fat stored in adipose tissue.
  • In the digestive tract, skin, and kidneys, blood flow slows because they are less vital.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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