Chemistry:5-Methoxytryptamine

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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.[1] It has been shown to occur naturally in the body in low levels, especially in the pineal gland.[1][2] It is formed via O-methylation of serotonin or N-deacetylation of melatonin.[1][3][2]

5-MT is a highly potent and non-selective serotonin receptor agonist[4][5][6][7] and shows serotonergic psychedelic-like effects in animals.[8] However, it is inactive in humans, at least orally, likely due to rapid metabolism by monoamine oxidase (MAO).[9][10] 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.[1][3] It is also a precursor of 5-MeO-DMT in some species.[1]

Pharmacology

Pharmacodynamics

5-MT activities
Target Affinity (Ki, nM)
5-HT1A 3.2–4.8 (Ki)
183–535 (EC50)
66–135% (Emax)
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)
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 (non-human)
5-HT4 27–2,443 (Ki)
437 (EC50) (pig)
107% (Emax) (pig)
5-HT5A 98 (unknown)
5-HT6 18–88
5-HT7 0.5–5.0
MT1 >10,000
MT2 >10,000
SERT 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: [4][5][6][7][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.[6] This was more potent than any other tryptamine evaluated in two large series of compounds.[6][7] 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).[7]

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.[1][3]

5-MT shows dramatically reduced activity as a monoamine releasing agent compared to tryptamine and serotonin.[6]

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.[8][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.[1][11][40] It produces various other effects in animals as well.[1]

Pharmacokinetics

Distribution

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

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.[9][10]

Metabolites of 5-MT include 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol.[1][14] It may also be metabolized into melatonin.[1][3]

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).[43]

The predicted log P of 5-MT is 0.5 to 1.41.[43][44][45]

Analogues and derivatives

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.[10] 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

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Is 5-methoxytryptamine a pineal hormone?". Psychoneuroendocrinology 8 (1): 61–73. 1983. doi:10.1016/0306-4530(83)90041-0. PMID 6136058. 
  2. ↑ 2.0 2.1 "Day-night rhythm of 5-methoxytryptamine biosynthesis in the pineal gland of the golden hamster (Mesocricetus auratus).". J. Endocrinol. 118 (3): 389–397. 1988. doi:10.1677/joe.0.1180389. PMID 2460575. 
  3. ↑ 3.0 3.1 3.2 3.3 "On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species". J Pineal Res 61 (1): 27–40. August 2016. doi:10.1111/jpi.12336. PMID 27112772. 
  4. ↑ 4.0 4.1 "PDSP Database" (in zu). https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=5-methoxytryptamine&kiAllRadio=all&doQuery=Submit+Query. 
  5. ↑ 5.0 5.1 "BindingDB BDBM82087 2-(5-methoxy-1H-indol-3-yl)ethanamine::5-MT::5-Methoxytryptamine hydrochloride::CAS_66-83-1::tryptamine, 5-Methoxy". https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=82087. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorg Med Chem Lett 24 (19): 4754–4758. October 2014. doi:10.1016/j.bmcl.2014.07.062. PMID 25193229. 
  7. ↑ 7.0 7.1 7.2 7.3 "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology (Berl) 231 (21): 4135–4144. October 2014. doi:10.1007/s00213-014-3557-7. PMID 24800892. 
  8. ↑ 8.0 8.1 "5-Methoxytryptamine-induced head twitches in rats". Pol J Pharmacol Pharm 29 (3): 253–261. 1977. PMID 267911. 
  9. ↑ 9.0 9.1 "Structure–activity relationships of serotonin 5-HT 2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1 (5): 559–579. 2012. doi:10.1002/wmts.42. ISSN 2190-460X. 
  10. ↑ 10.0 10.1 10.2 "Chemistry and Structure–Activity Relationships of Psychedelics". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. 36. 2018. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. 
  11. ↑ 11.0 11.1 11.2 11.3 "The concentration of 5-methoxytryptamine in rat brain and its effects on behaviour following its peripheral injection". Neuropharmacology 14 (8): 601–606. August 1975. doi:10.1016/0028-3908(75)90127-6. PMID 126386. 
  12. ↑ 12.0 12.1 12.2 12.3 "Deamination of 5-methoxytryptamine, serotonin and phenylethylamine by rat MAO in vitro and in vivo". Life Sci 22 (7): 561–569. February 1978. doi:10.1016/0024-3205(78)90334-x. PMID 272480. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "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. February 1979. 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. ↑ 14.0 14.1 14.2 14.3 14.4 "5-Methoxytryptamine is metabolized by monoamine oxidase A in the pineal gland and plasma of golden hamsters". Neurosci Lett 123 (2): 172–174. February 1991. doi:10.1016/0304-3940(91)90923-h. PMID 2027530. 
  15. ↑ 15.0 15.1 15.2 "Head twitches produced by serotonergic drugs and opiates after lesion of the mesostriatal serotonergic system of the rat". Pol J Pharmacol Pharm 31 (4): 413–423. 1979. PMID 316525. 
  16. ↑ 16.0 16.1 16.2 "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. 1984. PMID 6152672. 
  17. ↑ "Medicinal chemistry of 5-HT5A receptor ligands: a receptor subtype with unique therapeutical potential". Curr Top Med Chem 10 (5): 554–578. 2010. doi:10.2174/156802610791111588. PMID 20166946. 
  18. ↑ "5-HT2A, 5-HT2B and 5-HT2C receptor ligands". Pharmacochemistry Library. 27. Elsevier. 1997. pp. 161–197. doi:10.1016/s0165-7208(97)80013-x. ISBN 978-0-444-82041-9. 
  19. ↑ "Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors". Synapse 35 (2): 144–150. February 2000. doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K. PMID 10611640. 
  20. ↑ "Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium". Br J Pharmacol 110 (3): 1023–1030. November 1993. doi:10.1111/j.1476-5381.1993.tb13916.x. PMID 8298790. 
  21. ↑ "Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle". Br J Pharmacol 112 (1): 323–331. May 1994. doi:10.1111/j.1476-5381.1994.tb13072.x. PMID 8032658. 
  22. ↑ "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. 1988. doi:10.1016/0304-3940(88)90185-1. PMID 2966313. 
  23. ↑ "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. 1997. doi:10.1016/S0014-2999(97)00029-0. PMID 9128844. 
  24. ↑ "Characterization of the contractile response induced by 5-methoxytryptamine in rat stomach fundus strips.". Eur J Pharmacol 318 (2–3): 403–409. 1996. doi:10.1016/S0014-2999(96)00777-7. PMID 9016931. 
  25. ↑ "5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum.". Naunyn-Schmiedeberg's Arch Pharmacol 342 (1): 9–16. 1990. doi:10.1007/bf00178965. PMID 2402303. 
  26. ↑ "Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells.". Neuropharmacology 36 (4–5): 713–720. 1997. doi:10.1016/S0028-3908(97)00019-1. PMID 9225298. 
  27. ↑ "[3H-Mesulergine labels 5-HT7 sites in rat brain and guinea-pig ileum but not rat jejunum."]. Br J Pharmacol 126 (1): 179–188. 1999. doi:10.1038/sj.bjp.0702293. PMID 10051134. 
  28. ↑ "Serotonin Receptor Subtypes and Ligands". American College of Neurophyscopharmacology. 2000-01-01. http://www.acnp.org/g4/GN401000039/Ch039.html. 
  29. ↑ "Central serotonin receptors as targets for drug research". J Med Chem 30 (1): 1–12. January 1987. doi:10.1021/jm00384a001. PMID 3543362. "Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites". 
  30. ↑ Encyclopedia of Signaling Molecules. Cham: Springer International Publishing. 2018. doi:10.1007/978-3-319-67199-4. ISBN 978-3-319-67198-7. https://inserm.hal.science/inserm-03986853. "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." 
  31. ↑ "Recent progress in the development of agonists and antagonists for melatonin receptors". Curr Med Chem 19 (21): 3532–3549. 2012. doi:10.2174/092986712801323153. PMID 22680635. 
  32. ↑ "Development of Agonists and Antagonists for Melatonin Receptors". Melatonin and Melatonergic Drugs in Clinical Practice. New Delhi: Springer India. 2014. pp. 97–116. doi:10.1007/978-81-322-0825-9_7. ISBN 978-81-322-0824-2. 
  33. ↑ "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. April 1978. doi:10.1111/j.2042-7158.1978.tb13219.x. PMID 24719. 
  34. ↑ 34.0 34.1 "On the central antiserotonin activity of benzoctamine and opipramol". Pol J Pharmacol Pharm 30 (6): 781–790. 1978. PMID 582625. 
  35. ↑ "On the central antiserotonin action of trazodone". Pol J Pharmacol Pharm 31 (1): 25–33. 1979. PMID 482164. 
  36. ↑ 36.0 36.1 "The central action of pizotifen". Psychopharmacology (Berl) 62 (3): 295–300. April 1979. doi:10.1007/BF00431961. PMID 111296. 
  37. ↑ "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. 1977. doi:10.1016/0028-3908(77)90142-3. 
  38. ↑ TiHKAL: The Continuation. Transform Press. 1997. ISBN 978-0-9630096-9-2. https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000532880-Alexander_Shulgin_and_Ann_Shulgin_-_TiHKAL.pdf. 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." 
  39. ↑ "5-MeO-T - PiHKAL·info". 11 November 2024. https://isomerdesign.com/pihkal/explore/5143. 
  40. ↑ "5-Methoxytryptamine: stimulation of 5-HT receptors mediating the rat hyperactivity syndrome and blood platelet aggregation". Adv Biochem Psychopharmacol 15: 127–140. 1976. PMID 15408. 
  41. ↑ "Physiological disposition of 5-methoxytryptamine and the rope climbing performance of rats". Psychopharmacologia 15 (2): 88–95. 1969. doi:10.1007/BF00407040. PMID 5351124. 
  42. ↑ "Potentiation by deprenyl of the autoreceptor-mediated inhibition of [3H]-5-hydroxytryptamine release by 5-methoxytryptamine". Naunyn Schmiedebergs Arch Pharmacol 333 (3): 330–333. July 1986. doi:10.1007/BF00512949. PMID 3093900. 
  43. ↑ 43.0 43.1 "5-Methoxytryptamine". https://pubchem.ncbi.nlm.nih.gov/compound/1833. 
  44. ↑ "Metabolite 5-Methoxytryptamine". https://go.drugbank.com/metabolites/DBMET01359. 
  45. ↑ "5-Methoxytryptamine". 10 June 2024. https://www.chemspider.com/Chemical-Structure.1767.html. 

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