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.
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 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]
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]
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]
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]
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 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]
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]
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 [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 | ![]() |
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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.
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 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]
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]
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]
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]
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 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]
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]
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 [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 | ![]() |
![]() | This is a user sandbox of
Kwingfield. You can use it for testing or practicing edits. This is not the sandbox where you should draft your assigned article for a dashboard.wikiedu.org course. To find the right sandbox for your assignment, visit your Dashboard course page and follow the Sandbox Draft link for your assigned article in the My Articles section. |
{{
cite journal}}
: CS1 maint: unflagged free DOI (
link)
{{
cite journal}}
: CS1 maint: unflagged free DOI (
link)
{{
cite web}}
: |last2=
has numeric name (
help)CS1 maint: numeric names: authors list (
link)
{{
cite web}}
: CS1 maint: url-status (
link)