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Tryptamine

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Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan.[1][2] The chemical structure is defined by an indole - a fused benzene and pyrrole ring, and a 2-aminoethyl group at the third carbon.[1] 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.[1][3][4] [5] Various amounts of tryptamine and related indolamine alkaloids are present in plants, fungi and animals.[6] Tryptamine has been shown to activate trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of 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.[2][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][6]

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

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

Mammalian Brain

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Endogenous levels of tryptamine in the mammalian brain are less than 100ng per gram of tissue.[4] [8] However, elevated levels of trace amines have been observed in neuropsychiatric disorders, such as bipolar depression and schizophrenia.[14]

Mammalian Gut Microbiome

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Tryptamine is relatively abundant in the gut and feces of humans and rodents.[2][9] 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.[2] Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.[9]

Metabolism of Tryptamine

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

Biosynthesis

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To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan.[4] Synthetic modifications to tryptamine can produce serotonin and melatonin, however it is not the main pathway of endogenous neurotransmitter synthesis.[15]

Catabolism

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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.[16]

Mechanism of Action and Biological Effects

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Neuromodulation

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Tryptamine can weakly activate the trace amine-associated receptor, TAAR1 (hTAAR1 in humans).[17][7][18] 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.[18] [14]

hTAAR1

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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.[8] Tryptamine and other hTAAR1 agonists can increase neuronal firing by inhibiting neurotransmitter recycling through cAMP-dependent phosphorylation of the monoamine reuptake transporter.[19] [14] This mechanism increases the amount of neurotransmitter in the synaptic cleft, subsequently increasing postsynaptic receptor binding and neuronal activation.[14] 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.[14] The balance between the inhibitory and excitatory activity of hTAAR1 activation highlights the role of tryptamine in the regulation of neural activity.[20]

Activation of hTAAR1 is under investigation as a novel treatment for depression, addiction and schizophrenia.[21] 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).[21] Additionally, the hTAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia.[22] 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.[20] [22]

Gastrointestinal Motility

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Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium.[9] 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.[9] GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).[9] cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.[10][23]

Pharmacokinetics

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TAAR1 Activation (EC50) and Binding Affinity (Ki) of Tryptamines[22]
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

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Drug Mechanism Treatment Effect Structure
Sumatriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Sumatriptan
Rizatriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Rizatriptan
Zolmitriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Zolmitriptan
Almotriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Almotriptan
Eletriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Eletriptan
Frovatriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Frovatriptan
Naratriptan[11] 5-HT1B and 5-HT1D agonist Migraine Headaches Vasoconstriction of brain blood vessels
Naratriptan

See also

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  1. ^ a b c PubChem. "Tryptamine". pubchem.ncbi.nlm.nih.gov. Retrieved 2020-12-01.
  2. ^ a b c d 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). doi:10.3390/nu8010056. ISSN 2072-6643. PMC 4728667. PMID 26805875.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ 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.
  4. ^ a b c 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.
  5. ^ "The Ayahuasca Phenomenon". MAPS. Retrieved 2020-10-03.
  6. ^ a b Kousara, Shazia; Anjuma, Sadia Noreen; Jaleela, Farrukh; Khana, Jallat; Naseema, Sidra (2017). "Biomedical Significance of Tryptamine: A Review". Journal of Pharmacovigilance. 5 (5). doi:10.4172/2329-6887.1000239. ISSN 2329-6887.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ a b Khan, Muhammad Zahid; Nawaz, Waqas (2016-10-01). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomedicine & Pharmacotherapy. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. ISSN 0753-3322.
  8. ^ a b c "Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges". Pharmacology & Therapeutics. 180: 161–180. 2017-12-01. doi:10.1016/j.pharmthera.2017.07.002. ISSN 0163-7258.
  9. ^ a b c d e f 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. PMID 29902441.
  10. ^ a b 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. PMID 12671039.
  11. ^ a b c d e f g h "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
  12. ^ "New Compound Related to Psychedelic Ibogaine Could Treat Addiction, Depression". UC Davis. 2020-12-09. Retrieved 2020-12-11.
  13. ^ ServiceDec. 9, Robert F.; 2020; Am, 11:45 (2020-12-09). "Chemists re-engineer a psychedelic to treat depression and addiction in rodents". Science | AAAS. Retrieved 2020-12-11. {{cite web}}: |last2= has numeric name (help)CS1 maint: numeric names: authors list (link)
  14. ^ a b c d e Miller, Gregory M. (2011). "The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity". Journal of neurochemistry. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. ISSN 0022-3042. PMC 3005101. PMID 21073468.
  15. ^ "Serotonin Synthesis and Metabolism". Sigma Aldrich. 2020.{{cite web}}: CS1 maint: url-status (link)
  16. ^ "MetaCyc L-tryptophan degradation VI (via tryptamine)". biocyc.org. Retrieved 2020-12-11.
  17. ^ Yu, Ai-Ming; Granvil, Camille P.; Haining, Robert L.; Krausz, Kristopher W.; Corchero, Javier; Küpfer, Adrian; Idle, Jeffrey R.; Gonzalez, Frank J. (2003-02-01). "The Relative Contribution of Monoamine Oxidase and Cytochrome P450 Isozymes to the Metabolic Deamination of the Trace Amine Tryptamine". Journal of Pharmacology and Experimental Therapeutics. 304 (2): 539–546. doi:10.1124/jpet.102.043786. ISSN 0022-3565. PMID 12538805.
  18. ^ a b Zucchi, R; Chiellini, G; Scanlan, T S; Grandy, D K (2006). "Trace amine-associated receptors and their ligands". British Journal of Pharmacology. 149 (8): 967–978. doi:10.1038/sj.bjp.0706948. ISSN 0007-1188. PMC 2014643. PMID 17088868.
  19. ^ Jing, Li; Li, Jun-Xu (2015-08-15). "Trace amine-associated receptor 1: a promising target for the treatment of psychostimulant addiction". European journal of pharmacology. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. ISSN 0014-2999. PMC 4532615. PMID 26092759.
  20. ^ a b Grandy, David K.; Miller, Gregory M.; Li, Jun-Xu (2016-02-01). ""TAARgeting Addiction" The Alamo Bears Witness to Another Revolution". Drug and alcohol dependence. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. ISSN 0376-8716. PMC 4724540. PMID 26644139.
  21. ^ a b "Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges". Pharmacology & Therapeutics. 180: 161–180. 2017-12-01. doi:10.1016/j.pharmthera.2017.07.002. ISSN 0163-7258.
  22. ^ a b c 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.
  23. ^ "Microbiome-Lax May Relieve Constipation". GEN - Genetic Engineering and Biotechnology News. 2018-06-15. Retrieved 2020-12-11.
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