Tryptamine

Last updated
Tryptamine
Tryptamine structure.svg
Tryptamine-3d-sticks.png
Names
Preferred IUPAC name
2-(1H-Indol-3-yl)ethan-1-amine
Identifiers
3D model (JSmol)
125513
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.464 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C10H12N2/c11-6-5-8-7-12-10-4-2-1-3-9(8)10/h1-4,7,12H,5-6,11H2 Yes check.svgY
    Key: APJYDQYYACXCRM-UHFFFAOYSA-N X mark.svgN
  • InChI=1/C10H12N2/c11-6-5-8-7-12-10-4-2-1-3-9(8)10/h1-4,7,12H,5-6,11H2
    Key: APJYDQYYACXCRM-UHFFFAOYAU
  • c1ccc2c(c1)c(c[nH]2)CCN
Properties [1]
C10H12N2
Molar mass 160.220 g·mol−1
Appearancewhite to orange needles
Melting point 118˚C
Boiling point 137 °C (279 °F; 410 K) (0.15 mmHg)
negligible solubility in water
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. [2] [3] The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen). [2] The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others. [4] [5] [6] Tryptamine has been shown to activate trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems. [7] [8] In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility. [3] [9] [10] Multiple tryptamine-derived drugs have been developed to treat migraines, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders. [11] [12] [13]

Contents

All tryptamine derivatives possess a modified 2-aminoethyl group and/or the addition of a substituent on the indole. Tryptamine Alkaloids 2.png
All tryptamine derivatives possess a modified 2-aminoethyl group and/or the addition of a substituent on the indole.

Natural occurrences

For a list of plants, fungi and animals containing tryptamines, see List of psychoactive plants and List of naturally occurring tryptamines.

Mammalian brain

Endogenous levels of tryptamine in the mammalian brain are less than 100 ng per gram of tissue. [14] [15] However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as bipolar depression and schizophrenia. [16]

Mammalian gut microbiome

Tryptamine is relatively abundant in the gut and feces of humans and rodents. [17] [18] Commensal bacteria, including Ruminococcus gnavus and Clostridium sporogenes in the gastrointestinal tract, possess the enzyme tryptophan decarboxylase, which aids in the conversion of dietary tryptophan to tryptamine. [17] Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions. [18]

Metabolism

Biosynthesis

To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan. [19] Synthetic modifications to tryptamine can produce serotonin and melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis. [20]

Conversion of tryptophan to tryptamine, followed by its degradation to indole-3-acetic acid Biosynthesis and degradation of tryptamine.png
Conversion of tryptophan to tryptamine, followed by its degradation to indole-3-acetic acid

Catabolism

Monoamine oxidases A and B are the primary enzymes involved in tryptamine metabolism to produce indole-3-acetaldehyde, however it is unclear which isoform is specific to tryptamine degradation. [21]

Mechanisms of action and biological effects

Neuromodulation

Tryptamine can weakly activate the trace amine-associated receptor, TAAR1 (hTAAR1 in humans). [22] [23] [24] Limited studies have considered tryptamine to be a trace neuromodulator capable of regulating the activity of neuronal cell responses without binding to the associated postsynaptic receptors. [24] [25]

hTAAR1

Tryptamine promotes intestinal motility by activating serotonin receptors in the gut to increase colonic secretions. Tryptamine mechanism of action in the human gut.png
Tryptamine promotes intestinal motility by activating serotonin receptors in the gut to increase colonic secretions.

hTAAR1 is a stimulatory G-protein coupled receptor (GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons. [26] Tryptamine and other hTAAR1 agonists can increase neuronal firing by inhibiting neurotransmitter recycling through cAMP-dependent phosphorylation of the monoamine reuptake transporter. [27] [25] This mechanism increases the amount of neurotransmitter in the synaptic cleft, subsequently increasing postsynaptic receptor binding and neuronal activation. [25] Conversely, when hTAAR1 are colocalized with G protein-coupled inwardly-rectifying potassium channels (GIRKs), receptor activation reduces neuronal firing by facilitating membrane hyperpolarization through the efflux of potassium ions. [25] The balance between the inhibitory and excitatory activity of hTAAR1 activation highlights the role of tryptamine in the regulation of neural activity. [28]

Activation of hTAAR1 is under investigation as a novel treatment for depression, addiction, and schizophrenia. [29] hTAAR1 is primarily expressed in brain structures associated with dopamine systems, such as the ventral tegmental area (VTA) and serotonin systems in the dorsal raphe nuclei (DRN). [29] Additionally, the hTAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia. [30] Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce anti-depressive activity, increased cognition, reduced stress and anti-addiction effects. [28] [30]

Gastrointestinal motility

Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium. [31] Upon tryptamine binding, the activated 5-HT4 receptor undergoes a conformational change which allows its Gs alpha subunit to exchange GDP for GTP, and its liberation from the 5-HT4 receptor and βγ subunit. [31] GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). [31] cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility. [32] [33]

Pharmacodynamics

TAAR1 Activation (EC50) and Binding Affinity (Ki) of Tryptamines [34]
TryptamineHuman TAAR1Mouse TAAR1Rat TAAR
EC50KiEC50KiEC50Ki
Tryptamine21N/A2.71.40.410.13
Serotonin>50N/A>50N/A5.2N/A
Psilocin>30N/A2.7170.921.4
DMT>10N/A1.23.31.522
EC50 and Ki values are in micromolar (μM). EC50 reflects the amount

of tryptamine required to elicit 50% of the maximum TAAR1 response.

The smaller the Ki value, the stronger the tryptamine binds to the receptor.

Tryptamine-based therapeutics

DrugMechanismTreatmentEffectStructure
Sumatriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Sumatriptan Sumatriptan.svg
Sumatriptan
Rizatriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Rizatriptan Rizatriptan.png
Rizatriptan
Zolmitriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Zolmitriptan Zolmitriptan.svg
Zolmitriptan
Almotriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Almotriptan Almotriptan skeletal.svg
Almotriptan
Eletriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Eletriptan Eletriptan skeletal.svg
Eletriptan
Frovatriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Frovatriptan Frovatriptan 2.png
Frovatriptan
Naratriptan [35] 5-HT1B and 5-HT1D agonistMigraine Headaches Vasoconstriction of brain blood vessels
Naratriptan Naratriptan.svg
Naratriptan

See also

Related Research Articles

<span class="mw-page-title-main">Serotonin</span> Monoamine neurotransmitter

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex, touching on diverse functions including mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

<span class="mw-page-title-main">Tyramine</span> Chemical compound

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in the human by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. Similarly, a heteroreceptor is sensitive to neurotransmitters and hormones that are not released by the cell on which it sits. A given receptor can act as either an autoreceptor or a heteroreceptor, depending upon the type of transmitter released by the cell on which it is embedded.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors, are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerable interest in academic and proprietary pharmaceutical research due to its role as the endogenous receptor for the trace amines phenethylamine, tyramine, and tryptamine – metabolic derivatives of the amino acids phenylalanine, tyrosine and tryptophan, respectively – ephedrine, as well as the synthetic psychostimulants, amphetamine, methamphetamine and methylenedioxymethamphetamine. In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones. TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.

<i>N</i>-Methylphenethylamine Chemical compound

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects. PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to be metabolized into nymphetamine (NMPEA) and not wasted on the weaker inactive metabolites.

<span class="mw-page-title-main">TAAR2</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 2 (TAAR2), formerly known as G protein-coupled receptor 58 (GPR58), is a protein that in humans is encoded by the TAAR2 gene. TAAR2 is coexpressed with Gα proteins; however, as of February 2017, its signal transduction mechanisms have not been determined.

<span class="mw-page-title-main">TAAR6</span> Protein and coding gene in humans

Trace amine associated receptor 6, also known as TAAR6, is a protein which in humans is encoded by the TAAR6 gene.

<span class="mw-page-title-main">TAAR5</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 5 is a protein that in humans is encoded by the TAAR5 gene. In vertebrates, TAAR5 is expressed in the olfactory epithelium.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">3-Methoxytyramine</span> Chemical compound

3-Methoxytyramine (3-MT), also known as 3-methoxy-4-hydroxyphenethylamine, is a human trace amine that occurs as a metabolite of the neurotransmitter dopamine. It is formed by the introduction of a methyl group to dopamine by the enzyme catechol-O-methyl transferase (COMT). 3-MT can be further metabolized by the enzyme monoamine oxidase (MAO) to form homovanillic acid (HVA), which is then typically excreted in the urine.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

<span class="mw-page-title-main">RO5166017</span> Chemical compound

RO-5166017 is a drug developed by Hoffmann-La Roche which acts as a potent and selective agonist for the trace amine-associated receptor 1, with no significant activity at other targets. This is important for the study of the TAAR1 receptor, as while numerous other compounds are known which act as TAAR1 agonists, such as methamphetamine, MDMA and 3-iodothyronamine, all previously known TAAR1 agonists are either weak and rapidly metabolized, or have strong pharmacological activity at other targets, making it very difficult to assess which effects are due to TAAR1 activation. The discovery of RO-5166017 allows purely TAAR1 mediated effects to be studied, and in animal studies it was shown to prevent stress-induced hyperthermia and block dopamine-dependent hyperlocomotion, as well as blocking the hyperactivity which would normally be induced by an NMDA antagonist. The experiment was done in dopamine transporter knockout mice, and since TAAR1 affects the dopamine transporter, the results could be very different in humans.

<span class="mw-page-title-main">EPPTB</span> Chemical compound

EPPTB (RO-5212773) is a drug developed by Hoffmann-La Roche which acts as a potent and selective inverse agonist of trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. EPPTB is one of the first selective antagonists developed for TAAR1, and has been used to demonstrate an important role for TAAR1 in regulation of dopaminergic signalling in the limbic system. Although EPPTB has high affinity for the mouse TAAR1, it has much lower affinity for rat and human TAAR1, which limits its use in research. While the human and mouse forms of TAAR1 have similar functions and bind similar ligands, the actual binding affinities of individual ligands often vary significantly between the two versions of the receptor.

<i>o</i>-Phenyl-3-iodotyramine Chemical compound

o-Phenyl-3-iodotyramine (o-PIT) is a drug which acts as a selective agonist for the trace amine-associated receptor 1. It has reasonable selectivity for TAAR1 but relatively low potency, and is rapidly metabolised in vivo, making it less useful for research than newer ligands such as RO5166017.

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