Tryptamine

From Wikipedia, the free encyclopedia
This article is about the specific substance. For the class of substances, see substituted tryptamine.
Tryptamine
Tryptamine structure.svg
Tryptamine-3d-sticks.png
Names
Preferred IUPAC name
2-(1H-Indol-3-yl)ethan-1-amine
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.464 Edit this at Wikidata
IUPHAR/BPS
KEGG
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C10H12N2/c11-6-5-8-7-12-10-4-2-1-3-9(8)10/h1-4,7,12H,5-6,11H2 ☒N
    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
SMILES
  • c1ccc2c(c1)c(c[nH]2)CCN
Properties
Chemical formula
 C10H12N2
Molar mass 160.220 g·mol−1
Appearance white to orange crystalline powder[1]
Melting point 113-116˚C[1]
Boiling point 137 °C (279 °F; 410 K) (0.15 mmHg)[1]
Solubility in water
 negligible solubility in water[1]
Hazards
Flash point 185˚C[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N  (what is checkY☒N ?)
Infobox references

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 third carbon.[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.[2][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]

For a list of tryptamine derivatives, see: List of substituted tryptamines.

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 100ng per gram of tissue.[14] [15] However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders, 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 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]
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[]

  • Tryptophan
  • Substituted tryptamines
  • Trace amines
  • Serotonin receptor agonist
  • Human trace amine associated receptor 1
  • Neuromodulation

References[]

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  2. ^ a b c PubChem. "Tryptamine". pubchem.ncbi.nlm.nih.gov. Retrieved 2020-12-01.
  3. ^ a b Jenkins, Trisha A.; Nguyen, Jason C. D.; Polglaze, Kate E.; Bertrand, Paul P. (2016-01-20). "Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis". Nutrients. 8 (1): 56. doi:10.3390/nu8010056. ISSN 2072-6643. PMC 4728667. PMID 26805875.
  4. ^ Tylš, Filip; Páleníček, Tomáš; Horáček, Jiří (2014-03-01). "Psilocybin – Summary of knowledge and new perspectives". European Neuropsychopharmacology. 24 (3): 342–356. doi:10.1016/j.euroneuro.2013.12.006. ISSN 0924-977X. PMID 24444771. S2CID 10758314.
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  18. ^ a b Bhattarai, Yogesh; Williams, Brianna B.; Battaglioli, Eric J.; Whitaker, Weston R.; Till, Lisa; Grover, Madhusudan; Linden, David R.; Akiba, Yasutada; Kandimalla, Karunya K.; Zachos, Nicholas C.; Kaunitz, Jonathan D. (2018-06-13). "Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion". Cell Host & Microbe. 23 (6): 775–785.e5. doi:10.1016/j.chom.2018.05.004. ISSN 1931-3128. PMC 6055526. PMID 29902441.
  19. ^ Tittarelli, Roberta; Mannocchi, Giulio; Pantano, Flaminia; Romolo, Francesco Saverio (2015). "Recreational Use, Analysis and Toxicity of Tryptamines". Current Neuropharmacology. 13 (1): 26–46. doi:10.2174/1570159X13666141210222409. ISSN 1570-159X. PMC 4462041. PMID 26074742.
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  31. ^ a b c Bhattarai, Yogesh; Williams, Brianna B.; Battaglioli, Eric J.; Whitaker, Weston R.; Till, Lisa; Grover, Madhusudan; Linden, David R.; Akiba, Yasutada; Kandimalla, Karunya K.; Zachos, Nicholas C.; Kaunitz, Jonathan D. (2018-06-13). "Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion". Cell Host & Microbe. 23 (6): 775–785.e5. doi:10.1016/j.chom.2018.05.004. ISSN 1931-3128. PMC 6055526. PMID 29902441.
  32. ^ Field, Michael (2003). "Intestinal ion transport and the pathophysiology of diarrhea". Journal of Clinical Investigation. 111 (7): 931–943. doi:10.1172/JCI200318326. ISSN 0021-9738. PMC 152597. PMID 12671039.
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  34. ^ Gainetdinov, Raul R.; Hoener, Marius C.; Berry, Mark D. (2018-07-01). "Trace Amines and Their Receptors". Pharmacological Reviews. 70 (3): 549–620. doi:10.1124/pr.117.015305. ISSN 0031-6997. PMID 29941461. S2CID 49411553.
  35. ^ a b c d e f g "Serotonin Receptor Agonists (Triptans)", LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, PMID 31644023, retrieved 2020-10-15

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