Tryptamine, also known as 2-(3-indolyl)ethylamine, is an indolamine metabolite of the essential amino acid tryptophan. 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). 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. Tryptamine has been shown to activate serotonin receptors and trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems. In the human gut, bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility. 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.
Natural occurrences For a list of plants, fungi and animals containing tryptamines, see List of psychoactive plants and List of naturally occurring tryptamines.
Mammalian brain Endogenous levels of tryptamine in the mammalian brain are less than 100 ng per gram of tissue. However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as bipolar depression and schizophrenia.
Mammalian gut microbiome Tryptamine is relatively abundant in the gut and feces of humans and rodents. 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. Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.
Metabolism
Biosynthesis To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan. Synthetic modifications to tryptamine can produce serotonin and melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.
Catabolism 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.
Biological activity
Serotonin receptor agonist Tryptamine is known to act as a serotonin receptor agonist, although its potency is limited by rapid inactivation by monoamine oxidases. 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%). Tryptamine was of much lower potency in stimulating the 5-HT2A receptor β-arrestin pathway (EC50 = 3,485 ± 234 nM; Emax = 108 ± 16%). In contrast to the 5-HT2A receptor, tryptamine was found to be inactive at the serotonin 5-HT1A receptor.
Gastrointestinal motility Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium. 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. GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.
Monoamine releasing agent Tryptamine has been found to act as a monoamine releasing agent (MRA). It is a releaser of serotonin, dopamine, and norepinephrine, in that order of potency (EC50 = 32.6 nM, 164 nM, and 716 nM, respectively). That is, it acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).
Monoaminergic activity enhancer Tryptamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its serotonin receptor agonism. That is, it enhances the action potential-mediated release of these monoamine neurotransmitters. The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism. Synthetic and more potent MAEs like benzofuranylpropylaminopentane (BPAP) and indolylpropylaminopentane (IPAP) have been derived from tryptamine.
TAAR1 agonist Tryptamine is an agonist of the trace amine-associated receptor 1 (TAAR1). It is a potent TAAR1 full agonist in rats, a weak TAAR1 full agonist in mice, and a very weak TAAR1 partial agonist in humans. Tryptamine may act as a trace neuromodulator in some species via activation of TAAR1 signaling. The TAAR1 is a stimulatory G protein-coupled receptor (GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons. TAAR1 agonists have been implicated in regulating monoaminergic neurotransmission, for instance by activating G protein-coupled inwardly-rectifying potassium channels (GIRKs) and reducing neuronal firing via facilitation of membrane hyperpolarization through the efflux of potassium ions. TAAR1 agonists are under investigation as a novel treatment for neuropsychiatric conditions like schizophrenia, drug addiction, and depression. The TAAR1 is expressed in brain structures associated with dopamine systems, such as the ventral tegmental area (VTA) and serotonin systems in the dorsal raphe nuclei (DRN). Additionally, the human TAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia. Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce antipsychotic-like, anti-addictive, and antidepressant-like effects in animals.
Other actions Tryptamine has been found to act as a potent agonist of the GPR139 and to be involved in sleep regulation.
… excerpt ends here. Continue reading the full article.
