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.[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

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 3.2–4.8 (Ki)
183–535 (EC50Tooltip half-maximal effective concentration)
66–135% (EmaxTooltip 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)
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
SERTTooltip Serotonin transporter 4,000 (IC50Tooltip half-maximal inhibitory concentration)
2,169 (EC50)
NETTooltip Norepinephrine transporter >10,000 (IC50)
>10,000 (EC50)
DATTooltip 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][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 EC50Tooltip half-maximal effective concentration of 0.503Script error: No such module "String".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 3.87Script error: No such module "String".nM (7.7-fold lower) and dimethyltryptamine (DMT) had an EC50 of 38.3Script error: No such module "String".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

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

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.[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).[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.[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.

References

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  40. ↑ Script error: No such module "Citation/CS1".
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External links

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