Wikipedia

Tryptamine

(Redirected from Abramovitch-Shapiro tryptamine synthesis)
This article is about the specific substance. For the class of substances, see substituted tryptamine.

Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan.[9][10] 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).[9] 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.[11][12][13]

Tryptamine
Names
Preferred IUPAC name
2-(1H-Indol-3-yl)ethan-1-amine
Identifiers
3D model (JSmol)
125513
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.464 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C10H12N2/c11-6-5-8-7-12-10-4-2-1-3-9(8)10/h1-4,7,12H,5-6,11H2 checkY
    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
  • c1ccc2c(c1)c(c[nH]2)CCN
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
Pharmacology
Intravenous[2][3][4]
Pharmacokinetics:
Very low
Very rapid (oxidative deamination by MAOTooltip monoamine oxidase)[5][6][3][4]
Indole-3-acetic acid (IAA)
Very rapid[5][6][3][4]
Very short[5][6][3][4]
Very short[5][6][3][4]
Urine[4][7][8]
Legal status
  • Legal or unregulated
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Tryptamine has been shown to activate serotonin receptors[6][14] and trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems.[15][16] In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility.[10][17][18]

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.[19][20][21]

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 100 ng per gram of tissue.[22][23] However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as bipolar depression and schizophrenia.[24]

Mammalian gut microbiome

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Tryptamine is relatively abundant in the gut and feces of humans and rodents.[25][26] 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.[25] Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.[26]

Metabolism

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Biosynthesis

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To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan.[27] Synthetic modifications to tryptamine can produce serotonin and melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.[28]

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.[29]

Figure

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

Biological activity

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Tryptamine target activities
Target Affinity (Ki, nM) Species
5-HT1A 105 (Ki)
>10,000 (EC50Tooltip half-maximal effective concentration)		 Human
Human
5-HT1B 36–525 Human
5-HT1D 23–521 Human
5-HT1E 2,559 Human
5-HT1F 2,409 Human
5-HT2A 89–3,162 (Ki)
7.4 (EC50)		 Human
Human
5-HT2B 25–102 Human
5-HT2C 46–3,000 Human
5-HT3 ND ND
5-HT4 >10,000 Mouse
5-HT5A ND ND
5-HT6 70–438 Human
5-HT7 148–158 Human
α2A 19,000 Rat
TAAR1Tooltip Human trace amine-associated receptor 1 1,084 (Ki)
2,210–21,000 (EC50)		 Human
Human
SERTTooltip Serotonin transporter 32.6 (EC50) a Rat
NETTooltip Norepinephrine transporter 716 (EC50) a Rat
DATTooltip Dopamine transporter 164 (EC50) a Rat
Note: The smaller the value, the more avidly the compound binds to or activates the site. Footnotes: a = Neurotransmitter release. Refs: Main: [30][31] Additional: [32][6][33]

Serotonin receptor agonist

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Tryptamine is known to act as a serotonin receptor agonist, although its potency is limited by rapid inactivation by monoamine oxidases.[5][6][14][34][35] It has specifically been found to act as a full agonist of the serotonin 5-HT2A receptor (EC50Tooltip half-maximal effective concentration = 7.36 ± 0.56 nM; Emax = 104 ± 4%).[6] Tryptamine was of much lower potency in stimulating the 5-HT2A receptor β-arrestin pathway (EC50 = 3,485 ± 234 nM; Emax = 108 ± 16%).[6] In contrast to the 5-HT2A receptor, tryptamine was found to be inactive at the serotonin 5-HT1A receptor.[6]

Gastrointestinal motility

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Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium.[36] 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.[36] GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).[36] cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.[37][38]

 
Tryptamine promotes intestinal motility by activating serotonin receptors in the gut to increase colonic secretions.

TAAR1 agonist

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TAAR1 affinities and activational potencies of tryptamines[32]
Tryptamine Human TAAR1 Mouse TAAR1 Rat TAAR1
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
Dimethyltryptamine >10 N/A 1.2 3.3 1.5 22
Notes: (1) EC50 and Ki values are in micromolar (μM). (2) EC50 reflects the concentration required to elicit 50% of the maximum TAAR1 response. (3) The smaller the Ki value, the stronger the compound binds to the receptor.

Tryptamine can weakly activate the trace amine-associated receptor, TAAR1 (hTAAR1 in humans).[39][40][41] 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.[41][42]

hTAAR1 is a stimulatory G-protein coupled receptor (GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons.[43] Tryptamine and other hTAAR1 agonists can increase neuronal firing by inhibiting neurotransmitter recycling through cAMP-dependent phosphorylation of the monoamine reuptake transporter.[44][42] This mechanism increases the amount of neurotransmitter in the synaptic cleft, subsequently increasing postsynaptic receptor binding and neuronal activation.[42] 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.[42] The balance between the inhibitory and excitatory activity of hTAAR1 activation highlights the role of tryptamine in the regulation of neural activity.[45]

Activation of hTAAR1 is under investigation as a novel treatment for depression, addiction, and schizophrenia.[46] 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).[46] Additionally, the hTAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia.[32] 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.[45][32]

Monoamine releasing agent

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Monoamine release of tryptamine and related agents (EC50Tooltip Half maximal effective concentration, nM)
Compound 5-HTTooltip Serotonin NETooltip Norepinephrine DATooltip Dopamine Ref
Tryptamine 32.6 716 164 [6][33]
Serotonin 44.4 >10000 ≥1960 [47][48]
Phenethylamine >10000 10.9 39.5 [49][50][48]
Tyramine 2775 40.6 119 [47][48]
N-Methyltryptamine 22.4 733 321 [6]
Dimethyltryptamine 114 4166 >10000 [6]
Psilocin 561 >10000 >10000 [51][6]
Bufotenin 30.5 >10000 >10000 [6]
α-Methyltryptamine 21.7–68 79–112 78.6–180 [52]
α-Ethyltryptamine 23.2 640 232 [33]
D-Amphetamine 698–1765 6.6–7.2 5.8–24.8 [47][53]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [54][55]

Tryptamine has been found to act as a monoamine releasing agent.[5][6][33] 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).[5][6][33]

Monoaminergic activity enhancer

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Tryptamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its serotonin receptor agonism.[56][57] That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.[56][57] The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism.[58][59] Synthetic and more potent MAEs like benzofuranylpropylaminopentane (BPAP) and indolylpropylaminopentane (IPAP) have been derived from tryptamine.[56][57][60][61][62]

Effects in animals and humans

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In a published clinical study, tryptamine, at a total dose of 23 to 277 mg by intravenous infusion, produced hallucinogenic effects or perceptual disturbances similar to those of small doses of lysergic acid diethylamide (LSD).[2][3][6][4] It also produced other LSD-like effects, including pupil dilation, increased blood pressure, and increased force of the patellar reflex.[2][6][3][4] Tryptamine produced side effects including nausea, vomiting, dizziness, tingling sensations, sweating, and bodily heaviness among others as well.[2][4] Conversely, there were no changes in heart rate or respiratory rate.[4] The onset of the effects was rapid and the duration was very short.[5][6][3][4] This can be attributed to the very rapid metabolism of tryptamine by monoamine oxidase (MAO) and its very short elimination half-life.[5][6][3][4]

In animals, tryptamine, alone and/or in combination with a monoamine oxidase inhibitor (MAOI), produces behavioral changes such as hyperlocomotion and reversal of reserpine-induced behavioral depression.[2][5][63][64] In addition, it produces effects like hyperthermia, tachycardia, myoclonus, and seizures or convulsions, among others.[2][5][63][64] Findings on tryptamine and the head-twitch response in rodents are mixed, with some studies reporting no effect,[65][66] some reporting induction of head twitches by tryptamine,[67][68] and others reporting that tryptamine actually antagonized 5-hydroxytryptophan (5-HTP)-induced head twitches.[63][65] Head twitches in rodents are a behavioral proxy of psychedelic-like effects.[69][70] Many of the effects of tryptamine can be reversed by serotonin receptor antagonists like metergoline, metitepine (methiothepin), and cyproheptadine.[5][63][64][2] Conversely, the effects of tryptamine in animals are profoundly augmented by MAOIs due to inhibition of its metabolism.[5][64][2]

Tryptamine seems to also elevate prolactin and cortisol levels in animals and/or humans.[64]

The LD50Tooltip median lethal dose values of tryptamine in animals include 100 mg/kg i.p. in mice, 500 mg/kg s.c. in mice, and 223 mg/kg i.p. in rats.[71]

Pharmacokinetics

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Tryptamine produced endogenously or administered peripherally is readily able to cross the blood–brain barrier and enter the central nervous system.[64][63] This is in contrast to serotonin, which is peripherally selective.[64]

Tryptamine is metabolized by monoamine oxidase (MAO) to form indole-3-acetic acid (IAA).[64][5][63] Its metabolism is described as extremely rapid and its elimination half-life and duration as very short.[5][6][3][4] In addition, its duration is described as shorter than that of dimethyltryptamine (DMT).[2] Brain tryptamine levels are increased up to 300-fold by MAOIs in animals.[63] In addition, the effects of exogenous tryptamine are strongly augmented by monoamine oxidase inhibitors (MAOIs).[5][63]

Tryptamine is excreted in urine and its rate of urinary excretion has been reported to be pH-dependent.[4][7][8]

Chemistry

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Tryptamine is a substituted tryptamine derivative and trace amine and is structurally related to the amino acid tryptophan.

The experimental log P of tryptamine is 1.55.[71]

Derivatives

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Main article: Substituted tryptamine

The endogenous monoamine neurotransmitters serotonin (5-hydroxytryptamine or 5-HT) and melatonin (5-methoxy-N-acetyltryptamine), as well as trace amines like N-methyltryptamine (NMT), N,N-dimethyltryptamine (DMT), and bufotenin (N,N-dimethylserotonin), are derivatives of tryptamine.

A variety of drugs, including both naturally occurring and pharmaceutical substances, are derivatives of tryptamine. These include the tryptamine psychedelics like psilocybin, psilocin, DMT, and 5-MeO-DMT; tryptamine stimulants, entactogens, psychedelics, and/or antidepressants like α-methyltryptamine (αMT) and α-ethyltryptamine (αET); triptan antimigraine agents like sumatriptan; certain antipsychotics like oxypertine; and the sleep aid melatonin.

 
All tryptamine derivatives possess a modified 2-aminoethyl group and/or the addition of a substituent on the indole.

Various other drugs, including ergolines and lysergamides like the psychedelic lysergic acid diethylamide (LSD), the antimigraine agents ergotamine, dihydroergotamine, and methysergide, and the antiparkinsonian agents bromocriptine, cabergoline, lisuride, and pergolide; β-carbolines like harmine (some of which are monoamine oxidase inhibitors (MAOIs)); Iboga alkaloids like the hallucinogen ibogaine; yohimbans like the α2 blocker yohimbine; antipsychotics like ciclindole and flucindole; and the MAOI antidepressant metralindole, can all be thought of as cyclized tryptamine derivatives.

Drugs very closely related to tryptamines, but technically not tryptamines themselves, include certain triptans like avitriptan and naratriptan; the antipsychotics sertindole and tepirindole; and the MAOI antidepressants pirlindole and tetrindole.

References

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