Tryptamine
Metabolite of the amino acid tryptophan From Wikipedia, the free encyclopedia
Metabolite of the amino acid tryptophan From Wikipedia, the free encyclopedia
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]
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| Names | |
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| Preferred IUPAC name
2-(1H-Indol-3-yl)ethan-1-amine | |
| Identifiers | |
3D model (JSmol) |
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| 125513 | |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.000.464 |
| KEGG | |
PubChem CID |
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| UNII | |
CompTox Dashboard (EPA) |
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| 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).
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Tryptamine has been shown to activate serotonin receptors[7][8] and trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems.[9][10] In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility.[3][11][12]
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.[13][14][15]
For a list of plants, fungi and animals containing tryptamines, see List of psychoactive plants and List of naturally occurring tryptamines.
Endogenous levels of tryptamine in the mammalian brain are less than 100 ng per gram of tissue.[16][17] However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as bipolar depression and schizophrenia.[18]
Tryptamine is relatively abundant in the gut and feces of humans and rodents.[19][20] 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.[19] Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.[20]
To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan.[21] Synthetic modifications to tryptamine can produce serotonin and melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.[22]
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.[23]
Tryptamine is known to act as a serotonin receptor agonist, although its potency is limited by rapid inactivation by monoamine oxidases.[7][8][24][25] It has specifically been found to act as a full agonist of the serotonin 5-HT2A receptor (EC50 = 7.36 ± 0.56 nM; Emax = 104 ± 4%).[7] Tryptamine was of much lower potency in stimulating the 5-HT2A receptor β-arrestin pathway (EC50 = 3,485 ± 234 nM; Emax = 108 ± 16%).[7] In contrast to the 5-HT2A receptor, tryptamine was found to be inactive at the serotonin 5-HT1A receptor.[7] Alexander Shulgin tested tryptamine at high doses intravenously and found that it produced weak serotonergic psychedelic-like effects as well as peripheral nervous system changes.[7][26]
It can also weakly activate the trace amine-associated receptor, TAAR1 (hTAAR1 in humans).[27][28][29] 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.[29][30]
Tryptamine has been found to act as a monoamine releasing agent.[7][31] It is a releaser of serotonin, dopamine, and norepinephrine, in that order of potency (EC50 = 32.6 ± 2.6 nM, 164 ± 16 nM, and 716 ± 46 nM, respectively).[7][31] It is also a monoaminergic activity enhancer of these neurotransmitters.[32][33]
hTAAR1 is a stimulatory G-protein coupled receptor (GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons.[34] Tryptamine and other hTAAR1 agonists can increase neuronal firing by inhibiting neurotransmitter recycling through cAMP-dependent phosphorylation of the monoamine reuptake transporter.[35][30] This mechanism increases the amount of neurotransmitter in the synaptic cleft, subsequently increasing postsynaptic receptor binding and neuronal activation.[30] 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.[30] The balance between the inhibitory and excitatory activity of hTAAR1 activation highlights the role of tryptamine in the regulation of neural activity.[36]
Activation of hTAAR1 is under investigation as a novel treatment for depression, addiction, and schizophrenia.[37] 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).[37] Additionally, the hTAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia.[38] 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.[36][38]
Tryptamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its serotonin receptor agonism.[32][33] That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.[32][33] The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism.[39][40] Synthetic and more potent MAEs like benzofuranylpropylaminopentane (BPAP) and indolylpropylaminopentane (IPAP) have been derived from tryptamine.[32][33][41][42][43]
Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium.[44] 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.[44] GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).[44] cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.[45][46]
| 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. | ||||||
| Drug | Mechanism | Treatment | Effect | Structure |
|---|---|---|---|---|
| Sumatriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
| Rizatriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
| Zolmitriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
| Almotriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
| Eletriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
| Frovatriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
| Naratriptan[48] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels |  |
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