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Tryptamine
[edit]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.
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/5b/Tryptamine_Alkaloids_2.png/496px-Tryptamine_Alkaloids_2.png)
Natural Occurrences
[edit]For a list of plants, fungi and animals containing tryptamines, see: List of psychoactive plants and List of naturally occurring tryptamines.
Mammalian Brain
[edit]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
[edit]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
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/e/ed/Biosynthesis_and_degradation_of_tryptamine.png/491px-Biosynthesis_and_degradation_of_tryptamine.png)
Biosynthesis
[edit]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
[edit]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
[edit]Neuromodulation
[edit]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
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/0/09/Tryptamine_mechanism_of_action_in_the_human_gut.png/475px-Tryptamine_mechanism_of_action_in_the_human_gut.png)
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
[edit]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
[edit]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
[edit]Drug | Mechanism | Treatment | Effect | Structure |
---|---|---|---|---|
Sumatriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
Rizatriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
Zolmitriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
Almotriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
Eletriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
Frovatriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
Naratriptan[11] | 5-HT1B and 5-HT1D agonist | Migraine Headaches | Vasoconstriction of brain blood vessels | ![]() |
See also
[edit]- Tryptophan
- Substituted tryptamines
- Trace amines
- Serotonin receptor agonist
- Human trace amine associated receptor 1
- Neuromodulation
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- ^ a b c PubChem. "Tryptamine". pubchem.ncbi.nlm.nih.gov. Retrieved 2020-12-01.
- ^ 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.
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