5-Methoxytryptamine
5-Methoxytryptamine, also known as serotonin methyl ether or O-methylserotonin and as mexamine, is a tryptamine derivative closely related to the neurotransmitters serotonin and melatonin. It has been shown to occur naturally in the pineal gland of the brain. It is formed via O-methylation of serotonin or N-deacetylation of melatonin.
5-MT is a highly potent and non-selective serotonin receptor agonist and shows serotonergic psychedelic-like effects in animals. However, it is inactive in humans, at least orally, likely due to rapid metabolism by monoamine oxidase. The levels and effects of 5-MT are dramatically potentiated by monoamine oxidase inhibitors in animals.
Use and effects
5-MT is said to produce mild psychoactive effects in humans. It can reportedly potentiate the effects of other drugs such as LSD and THC.Biosynthesis
5-MT can be formed by O-methylation of serotonin mediated by hydroxyindole O-methyltransferase or by N-deacetylation of melatonin. It is also a precursor of 5-MeO-DMT in some species.Pharmacology
Pharmacodynamics
5-MT acts as an agonist of the serotonin 5-HT1, 5-HT2, 5-HT4, 5-HT6, and 5-HT7 receptors.It is an extremely potent serotonin 5-HT2A receptor agonist in vitro, with a of 0.5 nM or 0.7 nM. This was more potent than any other tryptamine evaluated in two large series of compounds. For comparison, 5-MeO-DMT had an of 3.87nM and dimethyltryptamine had an of 38.3nM.
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. Conversely, one assay reported comparable, low or sub-nanonomolar potencies for all three receptors and the 5-HT1A receptor.
5-MT, in contrast to the closely related melatonin, has no affinity for the melatonin receptors. Conversely, in tango assay it displayed agonist-like activity at MT1. However, it may also be converted into melatonin in the body, and hence may indirectly act as a melatonin receptor agonist.
5-MT shows dramatically reduced activity as a monoamine releasing agent compared to tryptamine and serotonin.
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. As such, it may be a hallucinogen in humans. However, in one recent study subcutaneous injection failed to increase HTRs under any conditions in mice, only inducing 5-HT1A-mediated hypothermia and hypolocomotion. 5-MT is only briefly mentioned in several places in Alexander Shulgin's TiHKAL and its psychoactive effects are not described. Besides psychedelic-like effects, 5-MT produces a "hyperactivity syndrome" in rodents. It produces various other effects in animals as well.Pharmacokinetics
Distribution
5-MT is able to cross the blood–brain barrier and enter the central nervous system with peripheral administration in animals. 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.Metabolism
5-MT is metabolized by deamination by monoamine oxidase, specifically monoamine oxidase A and to a much lesser extent by monoamine oxidase B.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. Similarly, levels of serotonin and phenethylamine were also greatly elevated by these drugs. 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.
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. Conversely, selegiline was ineffective in elevating brain or plasma 5-MT levels in hamsters.
The non-selective MAO-A and MAO-B inhibitor tranylcypromine has been frequently used to potentiate the effects of 5-MT in animal studies.
5-MT is orally inactive in humans presumably due to rapid metabolism by MAO-A.
Metabolites of 5-MT include 5-methoxyindole-3-acetic acid and 5-methoxytryptophol. It may also be metabolized into melatonin.
Chemistry
5-MT, also known as 5-methoxytryptamine or as 5-hydroxytrypamine O-methyl ether, is a substituted tryptamine and a derivative of serotonin and precursor of melatonin.The predicted log P of 5-MT is 0.5 to 1.41.