5-Methoxytryptamine

Last updated
5-Methoxytryptamine
5-methoxytryptamine.png
Clinical data
Other names5-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 Tooltip Monoamine oxidase A
Identifiers
  • 2-(5-Methoxy-1H-indol-3-yl)ethanamine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.009.231 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H14N2O
Molar mass 190.246 g·mol−1
3D model (JSmol)
  • O(c1cc2c(cc1)[nH]cc2CCN)C
  • InChI=1S/C11H14N2O/c1-14-9-2-3-11-10(6-9)8(4-5-12)7-13-11/h2-3,6-7,13H,4-5,12H2,1H3 Yes check.svgY
  • Key:JTEJPPKMYBDEMY-UHFFFAOYSA-N Yes check.svgY
   (verify)

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]

Contents

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

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

Pharmacodynamics

5-MT activities
Target Affinity (Ki, nM)
5-HT1A 3.2 (Ki)
183–535 (EC50 Tooltip half-maximal effective concentration
66–135% (Emax Tooltip maximal efficacy)
5-HT1B 0.75–38
5-HT1D 1.7–34
5-HT1E 3,151
5-HT1F 1,166
5-HT2A 4.8–724 (Ki)
0.503 (EC50)
119% (Emax)
5-HT2B 0.51–16
5-HT2C 45–943
5-HT3 >10,000 (non-human)
5-HT4 27–2,443
5-HT5A 98 (unknown)
5-HT6 18–88
5-HT7 0.5–5.0
MT1 >10,000
MT2 >10,000
SERT Tooltip Serotonin transporter4,000 (IC50 Tooltip half-maximal inhibitory concentration)
2,169 (EC50)
NET Tooltip Norepinephrine transporter>10,000 (IC50)
>10,000 (EC50)
DAT Tooltip Dopamine transporter>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]

5-MT acts as an agonist of the serotonin 5-HT1, 5-HT2, 5-HT4, 5-HT6, and 5-HT7 receptors. [18] [19] [20] [21] [22] [23] [24]

It is an extremely potent serotonin 5-HT2A receptor agonist in vitro , with an EC50 Tooltip half-maximal effective concentration 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. [25]

5-MT, in contrast to the closely related melatonin, has no affinity for the melatonin receptors. [26] [27] 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

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] [28] [29] [30] [31] [15] [16] As such, it may be a hallucinogen in humans. [32] 5-MT is only briefly mentioned in several places in Alexander Shulgin's TiHKAL and its psychoactive effects are not described. [33] [34] Besides psychedelic-like effects, 5-MT produces a "hyperactivity syndrome" in rodents. [3] [11] [35] It produces various other effects in animals as well. [3]

Pharmacokinetics

Distribution

5-MT is able to cross the blood–brain barrier and enter the central nervous system with peripheral administration in animals. [11]

Metabolism

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] [36]

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] [29] [31] [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

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). [37]

It 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.

The predicted log P of 5-MT is 0.5 to 1.41. [37] [38] [39]

References

  1. 1 2 3 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.
  2. 1 2 3 4 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.
  3. 1 2 3 4 5 6 7 8 9 10 Pévet P (1983). "Is 5-methoxytryptamine a pineal hormone?". Psychoneuroendocrinology. 8 (1): 61–73. doi:10.1016/0306-4530(83)90041-0. PMID   6136058.
  4. 1 2 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.
  5. 1 2 3 4 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.
  6. 1 2 "PDSP Database". UNC (in Zulu). Retrieved 3 December 2024.
  7. 1 2 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.
  8. 1 2 3 4 5 Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorg Med Chem Lett. 24 (19): 4754–4758. doi:10.1016/j.bmcl.2014.07.062. PMC   4211607 . PMID   25193229.
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  10. 1 2 Przegaliński E, Zebrowska-Lupina I, Wójcik A, Kleinrok Z (1977). "5-Methoxytryptamine-induced head twitches in rats". Pol J Pharmacol Pharm. 29 (3): 253–261. PMID   267911.
  11. 1 2 3 4 Green AR, Hughes JP, Tordoff AF (August 1975). "The concentration of 5-methoxytryptamine in rat brain and its effects on behaviour following its peripheral injection". Neuropharmacology. 14 (8): 601–606. doi:10.1016/0028-3908(75)90127-6. PMID   126386.
  12. 1 2 3 4 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.
  13. 1 2 3 4 5 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.
  14. 1 2 3 4 5 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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  16. 1 2 3 Kolasa K, Kleinrok Z, Rajtar G, Juszkiewicz M (1984). "Effects of histamine and H1 and H2-receptor antagonists on wet-dog-shake episodes in rats induced with tranylcypromine and 5-methoxytryptamine". Acta Physiol Pol. 35 (3): 225–230. PMID   6152672.
  17. ↑ Volk B, Nagy BJ, Vas S, Kostyalik D, Simig G, Bagdy G (2010). "Medicinal chemistry of 5-HT5A receptor ligands: a receptor subtype with unique therapeutical potential". Curr Top Med Chem. 10 (5): 554–578. doi:10.2174/156802610791111588. PMID   20166946.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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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  22. ↑ Boess FG, Monsma Jr FJ, Carolo C, Meyer V, Rudler A, Zwingelstein C, Sleight AJ (1997). "Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells". Neuropharmacology. 36 (4–5): 713–720. doi:10.1016/S0028-3908(97)00019-1. PMID   9225298. S2CID   41813873.
  23. ↑ Hemedah M, Coupar IM, Mitchelson FJ (1999). "[3H]-Mesulergine labels 5-HT7 sites in rat brain and guinea-pig ileum but not rat jejunum". Br J Pharmacol. 126 (1): 179–188. doi:10.1038/sj.bjp.0702293. PMC   1565797 . PMID   10051134.
  24. ↑ Glennon RA, Dukat M, Westkaemper RB (2000-01-01). "Serotonin Receptor Subtypes and Ligands". American College of Neurophyscopharmacology. Archived from the original on 21 April 2008. Retrieved 2008-04-11.
  25. ↑ Choi, Sangdun, ed. (2018). Encyclopedia of Signaling Molecules. Cham: Springer International Publishing. doi:10.1007/978-3-319-67199-4. ISBN   978-3-319-67198-7. 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.
  26. ↑ 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.
  27. ↑ Zlotos DP (2014). "Development of Agonists and Antagonists for Melatonin Receptors". Melatonin and Melatonergic Drugs in Clinical Practice. New Delhi: Springer India. pp. 97–116. doi:10.1007/978-81-322-0825-9_7. ISBN   978-81-322-0824-2.
  28. ↑ Nakamura M, Fukushima H (April 1978). "Effects of reserpine, para-chlorophenylalanine, 5,6-dihydroxytryptamine and fludiazepam on the head twitches induced by 5-hydroxytryptamine or 5-methoxytryptamine in mice". J Pharm Pharmacol. 30 (4): 254–256. doi:10.1111/j.2042-7158.1978.tb13219.x. PMID   24719.
  29. 1 2 Przegaliński E, Baran L, Palider W, Bigajska K (1978). "On the central antiserotonin activity of benzoctamine and opipramol". Pol J Pharmacol Pharm. 30 (6): 781–790. PMID   582625.
  30. ↑ 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.
  31. 1 2 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ "5-MeO-T - PiHKAL·info". Isomer Design. 11 November 2024. Retrieved 3 December 2024.
  35. ↑ Boullin DJ, Green AR (1976). "5-Methoxytryptamine: stimulation of 5-HT receptors mediating the rat hyperactivity syndrome and blood platelet aggregation". Adv Biochem Psychopharmacol. 15: 127–140. PMID   15408.
  36. ↑ 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.
  37. 1 2 "5-Methoxytryptamine". PubChem. Retrieved 3 December 2024.
  38. ↑ "Metabolite 5-Methoxytryptamine". DrugBank Online. Retrieved 3 December 2024.
  39. ↑ "5-Methoxytryptamine". ChemSpider. 10 June 2024. Retrieved 3 December 2024.