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5-Methoxytryptamine
View on Wikipediafrom Wikipedia
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| Clinical data | |
|---|---|
| Other names | 5-MeO-T; 5-OMe-T; 5-MeOT; 5-MeO-TPA; 5-MT; MT; 5-Hydroxytryptamine methyl ether; Serotonin methyl ether; O-Methylserotonin; O-Methyl-5-HT; Mexamine; Meksamin; Mekasamin; PAL-234 |
| Routes of administration | Orally inactive[1][2] |
| Drug class | Non-selective serotonin receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen |
| Pharmacokinetic data | |
| Metabolism | MAO-A |
| Identifiers | |
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| CAS Number | |
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| IUPHAR/BPS | |
| ChemSpider | |
| UNII | |
| KEGG | |
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| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.009.231 |
| Chemical and physical data | |
| Formula | C11H14N2O |
| Molar mass | 190.246 g·mol−1 |
| 3D model (JSmol) | |
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5-Methoxytryptamine (5-MT, 5-MeO-T, or 5-OMe-T), also known as serotonin methyl ether or O-methylserotonin and as mexamine, is a tryptamine derivative closely related to the neurotransmitters serotonin and melatonin.[3] It has been shown to occur naturally in the body in low levels, especially in the pineal gland.[3][4] It is formed via O-methylation of serotonin or N-deacetylation of melatonin.[3][5][4]
5-MT is a highly potent and non-selective serotonin receptor agonist[6][7][8][9] and shows serotonergic psychedelic-like effects in animals.[10] However, it is inactive in humans, at least orally, likely due to rapid metabolism by monoamine oxidase (MAO).[1][2] The levels and effects of 5-MT are dramatically potentiated by monoamine oxidase inhibitors (MAOIs) in animals.[11][12][13][14][15][16]
Biosynthesis
[edit]5-MT can be formed by O-methylation of serotonin mediated by hydroxyindole O-methyltransferase (HIOMT) or by N-deacetylation of melatonin.[3][5] It is also a precursor of 5-MeO-DMT in some species.[3]
Pharmacology
[edit]Pharmacodynamics
[edit]| Target | Affinity (Ki, nM) |
|---|---|
| 5-HT1A | 3.2–9 (Ki) 183–535 (EC50) 66–135% (Emax) |
| 5-HT1B | 0.75–38 |
| 5-HT1D | 1.7–34 |
| 5-HT1E | 397–3,151 |
| 5-HT1F | 1,166 |
| 5-HT2A | 4.8–724 (Ki) 0.503 (EC50) 96–119% (Emax) |
| 5-HT2B | 0.51–16 (Ki) 1.62 (EC50) (rat) 101% (Emax) (rat) |
| 5-HT2C | 7.1–943 100% (Emax) |
| 5-HT3 | >10,000 |
| 5-HT4 | 27–2,443 (Ki) 437 (EC50) (pig) 107% (Emax) (pig) |
| 5-HT5A | 45.5 98 (unknown) |
| 5-HT6 | 18–88 |
| 5-HT7 | 0.5–5.0 |
| MT1 | >10,000 |
| MT2 | >10,000 |
| α2A | 1,835 |
| α2B | >10,000 |
| α2C | 2,174 |
| D3 | >10,000 |
| D4 | 1,422 |
| H1, H3 | >10,000 |
| σ1, σ2 | >10,000 |
| KOR | >10,000 |
| SERT | >10,000 4,000 (IC50) 2,169 (EC50) |
| NET | >10,000 (IC50) >10,000 (EC50) |
| DAT | >10,000 (IC50) 11,031 (EC50) |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [6][7][8][9][17][18][19][20][21] | |
5-MT acts as an agonist of the serotonin 5-HT1, 5-HT2, 5-HT4, 5-HT6, and 5-HT7 receptors.[22][23][24][25][26][27][28][29]
It is an extremely potent serotonin 5-HT2A receptor agonist in vitro, with an EC50 of 0.503 nM.[8] This was more potent than any other tryptamine evaluated in two large series of compounds.[8][9] For comparison, 5-MeO-DMT had an EC50 of 3.87 nM (7.7-fold lower) and dimethyltryptamine (DMT) had an EC50 of 38.3 nM (76-fold lower).[9]
5-MT has been said to be 25- and 400-fold selective for the serotonin 5-HT2B receptor over the serotonin 5-HT2A and 5-HT2C receptors, respectively.[30]
5-MT, in contrast to the closely related melatonin, has no affinity for the melatonin receptors.[31][32] However, it may be converted into melatonin in the body, and hence may indirectly act as a melatonin receptor agonist.[3][5]
5-MT shows dramatically reduced activity as a monoamine releasing agent compared to tryptamine and serotonin.[8]
Effects in animals and humans
[edit]5-MT dose-dependently induces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents, and this effect is reversed by serotonin 5-HT2A receptor antagonists.[10][33][34][35][36][15][16] As such, it may be a hallucinogen in humans.[37] 5-MT is only briefly mentioned in several places in Alexander Shulgin's TiHKAL and its psychoactive effects are not described.[38][39] Besides psychedelic-like effects, 5-MT produces a "hyperactivity syndrome" in rodents.[3][11][40] It produces various other effects in animals as well.[3]
Pharmacokinetics
[edit]Distribution
[edit]5-MT is able to cross the blood–brain barrier and enter the central nervous system with peripheral administration in animals.[11] However, it has also been reported that 5-MT shows strong peripheral selectivity in animals comparable to serotonin and bufotenin and that its capacity to exert central effects is limited.[41]
Metabolism
[edit]5-MT is metabolized by deamination by monoamine oxidase (MAO), specifically monoamine oxidase A (MAO-A) and to a much lesser extent by monoamine oxidase B (MAO-B).[12][13][14][42]
Brain levels of 5-MT following central administration of 5-MT in rats were potentiated by 20-fold by the MAO-A inhibitor clorgyline and by 5.5-fold by the MAO-B inhibitor selegiline.[13][12] Similarly, levels of serotonin and phenethylamine were also greatly elevated by these drugs.[12][13] In accordance with the potentiation of brain levels of 5-MT by MAOIs, the behavioral effects of centrally administered 5-MT in rats, for instance in the conditioned avoidance response test, are markedly enhanced by MAOIs, including by the dual MAO-A and MAO-B inhibitor iproniazid and by clorgyline and selegiline.[13]
Similarly to rat findings, pineal gland levels of endogenous 5-MT are dramatically elevated by the MAO-A inhibitor clorgyline and by the dual MAO-A and MAO-B inhibitor pargyline in hamsters, and plasma levels of exogenous 5-MT are greatly elevated by these MAOIs as well.[14] Conversely, selegiline was ineffective in elevating brain or plasma 5-MT levels in hamsters.[14]
The non-selective MAO-A and MAO-B inhibitor tranylcypromine has been frequently used to potentiate the effects of 5-MT in animal studies.[11][34][36][15][16]
5-MT is orally inactive in humans presumably due to rapid metabolism by MAO-A.[1][2]
Metabolites of 5-MT include 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol.[3][14] It may also be metabolized into melatonin.[3][5]
Chemistry
[edit]5-MT, also known as 5-methoxytryptamine or as 5-hydroxytrypamine O-methyl ether, is a substituted tryptamine and a derivative of serotonin (5-hydroxytryptamine) and precursor of melatonin (N-acetyl-5-methoxytryptamine).[43]
The predicted log P of 5-MT is 0.5 to 1.41.[43][44][45]
Analogues and derivatives
[edit]5-MT is closely related to other 5-methoxylated tryptamines such as 5-MeO-NMT, 5-MeO-DMT, 5-MeO-DPT, 5-MeO-DiPT, 5-MeO-MiPT, 5-MeO-DALT, and 5-MeO-AMT. 5-MeO-AMT is orally active in humans, in contrast to 5-MT, and could be thought of as a sort of orally active form of 5-MT.[2] Some other notable analogues of 5-MT include tryptamine, 2-methyl-5-hydroxytryptamine, 5-benzyloxytryptamine, 5-carboxamidotryptamine, 5-methyltryptamine, 5-(nonyloxy)tryptamine, α-methyl-5-hydroxytryptamine, acetryptine (5-acetyltryptamine), and isamide (N-chloroacetyl-5-methoxytryptamine), among others.
See also
[edit]- Substituted tryptamine
- Serotonin (5-hydroxytryptamine; 5-HT)
- N-Acetylserotonin
- Melatonin (5-methoxy-N-acetyltryptamine)
References
[edit]- ^ a b c Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT 2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN 2190-460X.
- ^ a b c d Nichols DE (2018). "Chemistry and Structure–Activity Relationships of Psychedelics". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
- ^ a b c d e f g h i j Pévet P (1983). "Is 5-methoxytryptamine a pineal hormone?". Psychoneuroendocrinology. 8 (1): 61–73. doi:10.1016/0306-4530(83)90041-0. PMID 6136058.
- ^ a b Galzin AM, Eon MT, Esnaud H, Lee CR, Pévet P, Langer SZ (1988). "Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus)". J. Endocrinol. 118 (3): 389–397. doi:10.1677/joe.0.1180389. PMID 2460575.
- ^ a b c d Tan DX, Hardeland R, Back K, Manchester LC, Alatorre-Jimenez MA, Reiter RJ (August 2016). "On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species". J Pineal Res. 61 (1): 27–40. doi:10.1111/jpi.12336. PMID 27112772.
- ^ a b "PDSP Database". UNC (in Zulu). Retrieved 3 December 2024.
- ^ a b Liu T. "BindingDB BDBM82087 2-(5-methoxy-1H-indol-3-yl)ethanamine::5-MT::5-Methoxytryptamine hydrochloride::CAS_66-83-1::tryptamine, 5-Methoxy". BindingDB. Retrieved 3 December 2024.
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- ^ a b c d Prozialek WC, Vogel WH (February 1978). "Deamination of 5-methoxytryptamine, serotonin and phenylethylamine by rat MAO in vitro and in vivo". Life Sci. 22 (7): 561–569. doi:10.1016/0024-3205(78)90334-x. PMID 272480.
- ^ a b c d e Prozialeck WC, Vogel WH (February 1979). "MAO inhibition and the effects of centrally administered LSD, serotonin, and 5-methoxytryptamine on the conditioned avoidance response in rats". Psychopharmacology (Berl). 60 (3): 309–310. doi:10.1007/BF00426673. PMID 108709.
In contrast, MAO inhibition greatly increased brain levels of 5-HT and 5-MT (Prozialeck and Vogel, 1978). For instance, clorgyline and deprenyl increased brain levels of 5-HT 8.5-fold and 4.4-fold and of 5-MT 20-fold and 5-fold, respectively.
- ^ a b c d e Raynaud F, Pévet P (February 1991). "5-Methoxytryptamine is metabolized by monoamine oxidase A in the pineal gland and plasma of golden hamsters". Neurosci Lett. 123 (2): 172–174. doi:10.1016/0304-3940(91)90923-h. PMID 2027530.
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- ^ Medhurst AD, Kaumann AJ (November 1993). "Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium". Br J Pharmacol. 110 (3): 1023–1030. doi:10.1111/j.1476-5381.1993.tb13916.x. PMC 2175817. PMID 8298790.
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- ^ Wu PH, Gurevich N, Carlen PL (1988). "Serotonin-1A receptor activation in hippocampal CA1 neurons by 8-hydroxy-2-(di-n-propylamino)tetralin, 5-methoxytryptamine and 5-hydroxytryptamine". Neurosci. Lett. 86 (1): 72–76. doi:10.1016/0304-3940(88)90185-1. PMID 2966313. S2CID 21620262.
- ^ Yamada J, Sugimoto Y, Yoshikawa T, Horisaka K (1997). "Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in rats: involvement of the peripheral 5-HT2A receptor". Eur J Pharmacol. 323 (2–3): 235–240. doi:10.1016/S0014-2999(97)00029-0. PMID 9128844.
- ^ Amemiya N, Hatta S, Takemura H, Ohshika H (1996). "Characterization of the contractile response induced by 5-methoxytryptamine in rat stomach fundus strips". Eur J Pharmacol. 318 (2–3): 403–409. doi:10.1016/S0014-2999(96)00777-7. PMID 9016931.
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Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
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1-Structure and properties of 5-HT2B receptors: 1.1-Selective agonists: [...] - 5-Methoxytryptamine is also 25- and 400-fold selective over the 5-HT2A and 5-HT2C receptor sites, respectively.
- ^ Zlotos DP (2012). "Recent progress in the development of agonists and antagonists for melatonin receptors". Curr Med Chem. 19 (21): 3532–3549. doi:10.2174/092986712801323153. PMID 22680635.
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- ^ Baran L, Maj J, Rogóz Z, Skuza G (1979). "On the central antiserotonin action of trazodone". Pol J Pharmacol Pharm. 31 (1): 25–33. PMID 482164.
- ^ a b Przegaliński E, Baran L, Palider W, Siwanowicz J (April 1979). "The central action of pizotifen". Psychopharmacology (Berl). 62 (3): 295–300. doi:10.1007/BF00431961. PMID 111296.
- ^ De Montigny C, Aghajanian GK (1977). "Preferential action of 5-methoxytryptamine and 5-methoxydimethyltryptamine on presynaptic serotonin receptors: A comparative iontophoretic study with LSD and serotonin". Neuropharmacology. 16 (12): 811–818. doi:10.1016/0028-3908(77)90142-3.
- ^ Shulgin A (1997). TiHKAL: The Continuation (PDF). Transform Press. ISBN 978-0-9630096-9-2. Retrieved 2 November 2024.
One of its most broadly studied properties is that of protecting an experimental animal against the damage of being exposed to radiation. It was unexpectedly observed that our essential and favorite neurotransmitter serotonin was every bit as effective as a radioprotective agent. In efforts to make this natural compound more accessible to the damaged animal, it was studied as the unacetylated Omethyl ether. This simple compound, 5-methoxytryptamine (5-MeO-T, or Mexamine) has been mentioned under the recipe for 5-MeO-DMT in its possible effects in potentiating CNS-active drugs. But here it deserves to be highlighted for its protection against radiation. Two structural modification directions of 5-methoxytryptamine have been thoroughly explored. [...] A A 5-MeO-T anti-radiation, not a psychedelic ? [...] Removal of both methyl groups from the nitrogen gives 5- methoxytryptamine (5-MeO-T) which has been explored most extensively by Soviet researchers as a treatment for exposure to radiation; this aspect of its action is discussed and expanded upon in the commentary under Melatonin. It is also known by the trade name Mexamine and has been looked at as a potentiator of centrally active drugs.
- ^ "5-MeO-T - PiHKAL·info". Isomer Design. 11 November 2024. Retrieved 3 December 2024.
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- ^ Galzin AM, Langer SZ (July 1986). "Potentiation by deprenyl of the autoreceptor-mediated inhibition of [3H]-5-hydroxytryptamine release by 5-methoxytryptamine". Naunyn Schmiedebergs Arch Pharmacol. 333 (3): 330–333. doi:10.1007/BF00512949. PMID 3093900.
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External links
[edit]5-Methoxytryptamine
View on Grokipediafrom Grokipedia
Chemistry
Structure and nomenclature
5-Methoxytryptamine has the molecular formula CHNO and a molecular weight of 190.24 g/mol.[1] Its systematic IUPAC name is 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine.[1] The core structure of 5-methoxytryptamine is based on the indole ring system, consisting of a benzene ring fused to a five-membered pyrrole ring, with a methoxy group (-OCH) substituted at the 5-position and an ethylamine side chain (-CHCHNH) attached to the 3-position of the indole.[1] This configuration places it within the class of tryptamine derivatives, which share the indole-ethylamine backbone.[9] Structurally, 5-methoxytryptamine closely resembles serotonin (5-hydroxytryptamine), from which it differs by the replacement of the 5-hydroxyl group with a methoxy group via O-methylation.[10] It is also the deacetylated precursor to melatonin, known chemically as N-acetyl-5-methoxytryptamine.[11] Common names for the compound include 5-MT, mexamine, and O-methylserotonin.[1]Physical and chemical properties
5-Methoxytryptamine appears as a white to off-white crystalline solid, often described as a powder or crystal form depending on purification methods.[12][13] It has a melting point of 119–123 °C, which facilitates its handling in laboratory settings without decomposition under standard conditions.[1][14] The compound exhibits moderate solubility in polar solvents but limited solubility in water. Specifically, its water solubility is approximately 0.8 mg/mL at 25 °C, while it is highly soluble in ethanol (≥28 mg/mL) and DMSO (≥19–38 mg/mL). It is insoluble in non-polar solvents like hexane, reflecting its polar nature due to the amine and methoxy functional groups.[15][16][17]| Property | Value | Source |
|---|---|---|
| Appearance | White to off-white crystalline solid | TCI Chemicals[12]; Sigma-Aldrich[13] |
| Melting Point | 119–123 °C | PubChem (via HMDB)[1]; ChemicalBook[14] |
| Water Solubility | ~0.8 mg/mL at 25 °C | DrugBank (Chemaxon)[15] |
| Ethanol Solubility | ≥28 mg/mL | APExBIO[16] |
| DMSO Solubility | 19–38 mg/mL | APExBIO[16]; Selleckchem[17] |
Synthesis
One classical laboratory method for synthesizing 5-methoxytryptamine (5-MT) begins with 5-methoxyindole, which undergoes a Mannich reaction with formaldehyde and dimethylamine to afford 5-methoxygramine. This intermediate is quaternized with methyl iodide to form the methiodide salt, which is then displaced by cyanide ion to yield 5-methoxyindole-3-acetonitrile; subsequent reduction of the nitrile group, typically with lithium aluminum hydride or catalytic hydrogenation, provides 5-MT.[20] A direct route from serotonin involves selective O-methylation. Serotonin is deprotonated with sodamide in liquid ammonia to generate the phenoxide, followed by addition of methyl iodide to produce 5-MT in modest yields (around 20-30%). The key reaction proceeds as follows under anhydrous conditions: Post-reaction, the mixture is quenched with water, extracted, and the product isolated as the hydrochloride or picrate salt.[21] Challenges in these methylations include preventing over-methylation at the phenolic oxygen or unwanted reactions at the indole nitrogen, which can lead to N-methylated byproducts; these are minimized by using strong bases like sodamide to favor O-alkylation and conducting the reaction at low temperatures in non-protic solvents.[21] Alternative synthetic routes employ protecting group strategies, such as starting from 5-benzyloxyindole, which is converted to 5-benzyloxygramine via Mannich reaction, followed by side-chain elaboration to 5-benzyloxytryptamine; hydrogenolytic deprotection with palladium on carbon in ethanol yields serotonin, which is then O-methylated as described above to give 5-MT.[21] Routes from tryptophan derivatives typically involve initial conversion to 5-methoxyindole-3-acetic acid or its esters via methylation and decarboxylation, followed by reduction of the carboxylic acid or nitrile to the ethylamine side chain, though these are less direct and often lower yielding than indole-based methods.[22] The first syntheses of 5-MT were reported in the 1950s, notably by Benington, Morin, and Clark in 1958, during efforts to prepare serotonin analogs in connection with melatonin studies.[21]Biosynthesis and metabolism
Biosynthesis
5-Methoxytryptamine (5-MT) can be biosynthesized in the pineal gland through the O-methylation of serotonin, catalyzed by the enzyme hydroxyindole O-methyltransferase (HIOMT, also known as acetylserotonin O-methyltransferase or ASMT).[3] This reaction utilizes S-adenosylmethionine (SAM) as the methyl donor, producing 5-MT and S-adenosylhomocysteine (SAH) as a byproduct, as represented by the equation: The enzymatic mechanism follows an ordered Bi-Bi kinetic model, where SAM binds first to the enzyme, enhancing substrate affinity for serotonin.[23] HIOMT gene expression is predominantly localized in the pineal gland, with lower levels in the brain, and its activity is modulated by transcriptional regulation under circadian control.[24] An alternate biosynthetic pathway for melatonin involves the sequential conversion of serotonin to 5-MT by HIOMT, followed by N-acetylation of 5-MT to form melatonin, catalyzed by arylalkylamine N-acetyltransferase (AANAT).[3] Although this route is less dominant in mammals compared to the canonical pathway (serotonin to N-acetylserotonin via AANAT, then to melatonin via HIOMT), it contributes to 5-MT production as an intermediate, particularly under conditions where HIOMT activity precedes AANAT.[3] Biosynthesis of 5-MT exhibits a circadian rhythm, with peak production occurring at night, synchronized by the suprachiasmatic nucleus.[24] This rhythm is driven by nocturnal surges in norepinephrine release from sympathetic nerve terminals, which activates β-adrenergic receptors on pinealocytes, leading to increased cyclic AMP and subsequent upregulation of HIOMT and AANAT activities.[24] Daytime light exposure suppresses this process via photic inhibition of norepinephrine signaling.[24] 5-MT occurs naturally in the pineal gland and brain of mammals, as well as in various plants such as rice, where it serves as a precursor in indoleamine pathways.[25] In the golden hamster pineal gland, endogenous concentrations are low, approximately 10-20 ng/g tissue, reflecting its role as a transient intermediate prone to rapid metabolism.[26]Metabolism and distribution
5-Methoxytryptamine (5-MT) is lipophilic and rapidly crosses the blood-brain barrier following peripheral administration in rodents, allowing it to enter the central nervous system.[4] Levels are particularly elevated in the pineal gland, where 5-MT exhibits a diurnal rhythm with peak concentrations during the light phase in golden hamsters.[26] In rats, following intraperitoneal administration of 50 mg/kg, peak brain concentrations reach approximately 0.43 μg/g at 5 minutes, with over 90% clearance from plasma and tissues within 60 minutes.[27] In biological systems, 5-MT, derived briefly from serotonin as a biosynthetic intermediate, undergoes primary catabolic pathways including N-acetylation and oxidative deamination. Additionally, 5-MT can be produced by deacetylation of melatonin by aryl acylamidase in peripheral tissues such as the liver.[28] The N-acetylation of 5-MT to form melatonin (N-acetyl-5-methoxytryptamine) is catalyzed by arylalkylamine N-acetyltransferase (AANAT), utilizing acetyl-CoA as a cofactor: In plants, the homologous enzyme SNAT shows higher catalytic efficiency with 5-MT compared to serotonin, whereas in vertebrates, AANAT prefers serotonin as substrate.[3][29] Additionally, 5-MT is deaminated by monoamine oxidase (MAO) to yield 5-methoxyindoleacetic acid, a major inactive metabolite; this process is inhibited by MAO blockers such as pargyline.[30][27] Excretion of 5-MT occurs primarily via urinary elimination of its metabolites, including 5-methoxyindoleacetic acid. In rodents, the plasma half-life of 5-MT ranges from 15 to 19 minutes, consistent with rapid one-compartment kinetics observed in golden hamsters following administration.[31] Pharmacokinetically, 5-MT exhibits low plasma protein binding, characterized by weak, reversible interactions with high-capacity, low-affinity sites in human plasma.[32] Tissue distribution favors serotonin-rich regions; microdialysis studies in rats show that 5-MT administration into the raphe nuclei elevates extracellular serotonin levels in the frontal cortex (up to 800% of baseline) and striatum (up to 1000% of baseline), indicating accumulation and local metabolism in these areas.[33]Pharmacology
Pharmacodynamics
5-Methoxytryptamine (5-MT) acts primarily as a non-selective agonist at multiple serotonin (5-HT) receptor subtypes, exhibiting high affinity for several G protein-coupled receptors within the 5-HT family. It functions as a full agonist at the 5-HT1A, 5-HT2A, 5-HT4, 5-HT6, and 5-HT7 receptors, while displaying partial agonist activity at the 5-HT2C receptor. These interactions are supported by in vitro binding studies demonstrating nanomolar affinities across these subtypes.| Receptor Subtype | Ki Value (nM) | Species/Source | Reference |
|---|---|---|---|
| 5-HT1A | 2.5 | Rat cortex | PDSP Ki ID 159 |
| 5-HT2C | <50 | Human cloned | PDSP Database |
| 5-HT4 | 39.81 | Rat cloned | PDSP Ki ID 4040 |
| 5-HT6 | 18 | Human cloned | PDSP Ki ID 6512 |
| 5-HT7 | <10 | Human cloned | PMC 1574165 |
Pharmacokinetics
5-Methoxytryptamine demonstrates rapid absorption following parenteral administration in animal models, with peak plasma concentrations achieved within 5 minutes after intraperitoneal injection of 50 mg/kg in rats (5.3 μg/mL). Direct measurements of oral bioavailability are limited, but rapid intestinal uptake is suggested by animal data.[27] The compound exhibits high brain penetration, crossing the blood-brain barrier primarily via passive diffusion, with a cerebrospinal fluid-to-plasma ratio of approximately 0.5 in preclinical studies. In rats, brain tissue concentrations reach 0.43 μg/g at 5 minutes post-administration, indicating efficient central nervous system distribution.[27] Metabolism occurs predominantly in the liver through monoamine oxidase A (MAO-A)-mediated oxidative deamination and cytochrome P450 2D6 (CYP2D6)-catalyzed O-demethylation, with 5-methoxytryptophol identified as the major metabolite from the MAO pathway. This process is confirmed in the pineal gland and plasma of golden hamsters, where MAO-A inhibition elevates 5-methoxytryptamine levels while reducing 5-methoxytryptophol.[37][38] Elimination is primarily via renal clearance, with rapid disposition observed across species; in golden hamsters, plasma half-life ranges from 14.8 to 19.1 minutes following administration of 25 μg, while in rats over 90% clears from plasma and tissues within 60 minutes.[31][27] Pharmacokinetic effects are significantly modulated by monoamine oxidase inhibitors (MAOIs), which block metabolism and extend duration of action, as evidenced by elevated tissue levels and prolonged physiological responses in MAO-inhibited animals.[37]Research and applications
Animal studies
Preclinical research on 5-methoxytryptamine (5-MT) has primarily utilized rodent models to investigate its behavioral effects, revealing dose-dependent alterations in exploratory and stereotyped behaviors. In rats, subcutaneous administration of 5-MT at doses of 1-5 mg/kg induces head twitch responses, increased locomotion, and rearing activity, indicative of psychotomimetic effects mediated by 5-HT2A receptor activation.[39] Higher doses of 10-20 mg/kg elicit abnormal behaviors such as body shakes and limb jerks, alongside a dose-dependent reduction in overall locomotor activity.[5] Prenatal exposure in rats to 5-MT at 1.0 mg/kg leads to persistent behavioral changes, including altered exploratory patterns persisting into adolescence.[40] Physiological effects of 5-MT have been examined in feline models, where intravenous administration produces marked cutaneous vasodilation, analgesia, and hindlimb paralysis, with all effects lasting approximately 75 minutes.[27] These responses highlight 5-MT's potential to influence peripheral serotonin systems, though no significant cardiotoxicity has been observed in these acute administrations.[27] Neurochemically, 5-MT acts as a potent agonist at presynaptic 5-HT1A autoreceptors, thereby increasing serotonin release in the central nervous system of rodents.[26] In the pineal gland of golden hamsters, 5-MT biosynthesis exhibits a circadian rhythm, peaking nocturnally and contributing to modulation of serotonin turnover.[26] Toxicity studies in mice indicate an LD50 of approximately 106 mg/kg via intravenous route and 176 mg/kg intraperitoneally, with behavioral effects including somnolence, muscle weakness, and spasticity at sublethal doses around 45 mg/kg intravenously.[41] Oral LD50 values exceed 580 mg/kg, suggesting lower acute toxicity via this route.[42] Key animal studies from the 1980s, such as those in rat models, demonstrated 5-MT's capacity to produce psychedelic-like behaviors including head twitches following pargyline pretreatment, establishing its serotonergic profile.[5][39] More recent comparisons in the 2020s with structural analogs like 5-MeO-DMT in mice have shown that 5-MT analogs retain anxiolytic-like effects without full hallucinogenic potency when selectivity is shifted toward 5-HT1A receptors.[43]| Species | Route | Dose (mg/kg) | Key Effects |
|---|---|---|---|
| Rat | Subcutaneous | 1-5 | Head twitch, increased locomotion and rearing[39] |
| Rat | Subcutaneous | 10-20 | Body shakes, limb jerks, reduced locomotion[5] |
| Cat | Intravenous | N/A | Vasodilation, analgesia, hindlimb paralysis (duration ~75 min)[27] |
| Mouse | Intravenous | 45-106 | Somnolence, muscle weakness, LD50 at 106 mg/kg[41] |
| Mouse | Intraperitoneal | 176 | LD50, behavioral depression[44] |
| Golden Hamster | N/A (endogenous) | N/A | Circadian peak in pineal biosynthesis[26] |
Human studies and potential uses
Human studies on 5-methoxytryptamine (5-MT), also known as mexamine, are limited and primarily historical, with no large-scale randomized controlled trials conducted to date. Early research in the 1960s examined its presence in human blood and urine, detecting levels of 30–210 µg/24 h in patients with rheumatic fever, suggesting endogenous occurrence at low concentrations.[45] In the late 1950s and 1960s, 5-MT emerged in melatonin research as the immediate precursor to N-acetyl-5-methoxytryptamine (melatonin) via acetylation, and it was used as a research tool to explore serotonin pathways, including its role in antagonizing LSD-induced psychomimetic effects in human tolerance studies.[46] These investigations highlighted 5-MT's potential to abolish hallucinations and euphoria from LSD, indicating serotonergic modulation without inducing strong psychoactive effects itself at tested doses.[46] Anecdotal reports describe mild psychotomimetic experiences, such as visual distortions, euphoria, and altered perception, following oral doses of 10–20 mg, though formal trials are scarce and suggest 5-MT is largely orally inactive in humans due to rapid metabolism by monoamine oxidase A (MAO-A).[47] Outdated studies from the 1970s and early 1980s focused on peripheral effects, including vasodilation in vascular tissues, where 5-MT reduced noradrenaline release and induced hypotensive responses in animal models predictive of human cardiovascular influences, but no modern human data confirms these.[48] Gaps persist, with no evidence from contemporary clinical settings, underscoring the need for updated pharmacokinetic and safety profiling. Emerging therapeutic potential centers on 5-MT's agonism at 5-HT1A receptors, investigated for antidepressant and anxiolytic applications. Recent 2024 cryogenic electron microscopy (cryo-EM) structures of the 5-HT1A receptor bound to 5-methoxytryptamine analogs reveal binding modes that support non-hallucinogenic variants retaining anxiolytic-like and antidepressant-like efficacy in preclinical models of social defeat stress, positioning 5-MT derivatives as candidates for mood disorders without psychedelic side effects.[49] Additionally, 5-MT serves as a biosynthetic precursor to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in certain species, informing synthesis of therapeutic tryptamines. Derivatives like 5-MeO-DMT are under investigation in clinical trials for depression and PTSD, showing rapid antidepressant effects as of 2025.[50] As of 2025, 5-MT remains unscheduled in the US and EU, though it may face analog controls in jurisdictions prohibiting intent for human consumption due to its role in synthesizing controlled hallucinogens like 5-methoxy-N,N-diisopropyltryptamine.[51]Analogues and derivatives
5-Methoxytryptamine (5-MT) serves as a structural scaffold for several pharmacologically active analogues, particularly those with N-substitutions on the ethylamine side chain, which modify their interactions with serotonin receptors. Key analogues include 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a naturally occurring tryptamine found in the venom of the Colorado River toad (Incilius alvarius), noted for its potent agonism at 5-HT1A and 5-HT2A receptors.[52] Another is 5-methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT), a synthetic designer drug with reported psychedelic effects similar to other tryptamines, exhibiting affinity for 5-HT1A, 5-HT2A, and the serotonin transporter (SERT).[53] Similarly, 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), also known as Foxy, is an orally active hallucinogen that acts as an agonist at serotonin receptors including 5-HT1A (higher affinity) and lower affinity at 5-HT2A and 5-HT2C, with effects potentially involving serotonin transporter inhibition.[54][55] Derivatives of 5-MT include N-acetyl-5-methoxytryptamine, commonly known as melatonin, a hormone produced by the pineal gland that regulates circadian rhythms and lacks hallucinogenic properties due to its acetylation, which reduces serotonin receptor affinity.[56] In contrast, 4-hydroxy-5-methoxytryptamine (4-HO-5-MeO-T) is a serotonergic neurotoxin structurally related to 5-MT, capable of selectively damaging serotonin neurons through auto-oxidation and uptake via the serotonin transporter, similar to other hydroxylated tryptamines like 4,5-dihydroxytryptamine.[57] Structure-activity relationship studies of 5-methoxytryptamines reveal that the 5-methoxy group significantly enhances affinity and potency at the 5-HT1A receptor compared to unsubstituted tryptamines, contributing to anxiolytic and antidepressant effects.[52] N-substitution, such as dimethyl or diisopropyl groups, increases overall potency and hallucinogenic potential by improving 5-HT2A agonism, while certain modifications like fluorination or pyrrolidine rings can enhance 5-HT1A selectivity over 5-HT2A, reducing psychedelic effects.[58] These analogues and derivatives have diverse applications; for instance, 5-MeO-DiPT has been used recreationally as a synthetic hallucinogen, while selective 5-HT1A agonists derived from 5-MT, such as 4-fluoro-5-methoxy-pyrrolidino-tryptamine, show promise in preclinical models for treating anxiety and depression without inducing hallucinations.[52] 5-MeO-DMT is under investigation in clinical trials for neuropsychiatric disorders like PTSD due to its rapid-onset therapeutic effects.[59]| Compound | 5-HT1A EC50 (nM) or Ki (nM) | 5-HT2A EC50 (nM) or Ki (nM) | Primary Effects |
|---|---|---|---|
| 5-MeO-DMT | EC50: 25.6 (5-HT1A agonist) | Ki: ~1000 (moderate affinity) | Hallucinogenic, anxiolytic, antidepressant-like in rodents; intense psychedelic experiences in humans.[52][60] |
| 5-MeO-MiPT | Ki: ~100 (5-HT1A) | Ki: ~360 (5-HT2A) | Psychedelic with tactile enhancement; euphoria and sensory distortion reported anecdotally.[53][60] |
| 5-MeO-DiPT | Ki: ~100 (5-HT1A) | Ki: >10,000 (low affinity) | Auditory hallucinations prominent; stimulant-like at low doses, used recreationally as Foxy.[54][60] |