Tryptamine

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This article is about the specific substance. For the class of substances, see substituted tryptamine.
Tryptamine
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 Edit this at Wikidata
IUPHAR/BPS
KEGG
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 checkY
    Key: APJYDQYYACXCRM-UHFFFAOYSA-N ☒N
  • 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
Appearance white 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

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]

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 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

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.

hTAAR1 is a stimulatory

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]
Tryptamine Human TAAR1 Mouse TAAR1 Rat TAAR
EC50 Ki EC50 Ki EC50 Ki
Tryptamine 21 N/A 2.7 1.4 0.41 0.13
Serotonin >50 N/A >50 N/A 5.2 N/A
Psilocin >30 N/A 2.7 17 0.92 1.4
DMT >10 N/A 1.2 3.3 1.5 22
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

Drug Mechanism Treatment Effect Structure
Sumatriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Sumatriptan
Rizatriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Rizatriptan
Zolmitriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Zolmitriptan
Almotriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Almotriptan
Eletriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Eletriptan
Frovatriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Frovatriptan
Naratriptan[35] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Naratriptan

See also

References

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  13. ^ ServiceDec. 9, Robert F. "Chemists re-engineer a psychedelic to treat depression and addiction in rodents". Science | AAAS. Retrieved 2020-12-11.{{cite web}}: CS1 maint: numeric names: authors list (link)
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  20. ^ "Serotonin Synthesis and Metabolism". Sigma Aldrich. 2020.
  21. ^ "MetaCyc L-tryptophan degradation VI (via tryptamine)". biocyc.org. Retrieved 2020-12-11.
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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Tryptamine&oldid=1220463496"