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 Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

closely related to the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

. It has been shown to occur naturally in the body in low levels, especially in the

pineal gland The pineal gland (also known as the pineal body or epiphysis cerebri) is a small endocrine gland in the brain of most vertebrates. It produces melatonin, a serotonin-derived hormone, which modulates sleep, sleep patterns following the diurnal c ...

. It is formed via ''O''-

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

of serotonin or ''N''-

deacetylation : In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite react ...

of melatonin. 5-MT is a highly potent and non-selective

serotonin receptor agonist A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of t ...

and shows

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

-like effects in animals. However, it is inactive in humans, at least orally, likely due to rapid

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

(MAO). The levels and effects of 5-MT are dramatically potentiated by

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

s (MAOIs) in animals.

Biosynthesis

5-MT can be formed by ''O''-

mediated by hydroxyindole ''O''-methyltransferase (HIOMT) or by ''N''-

of melatonin. It is also a precursor of

5-MeO-DMT 5-MeO-DMT (5-methoxy-''N'',''N''-dimethyltryptamine), also known as ''O''-methylbufotenin or mebufotenin (), is a naturally occurring psychedelic of the tryptamine family. It is found in a wide variety of plant species, and is also secreted by ...

in some species.

Pharmacology

Pharmacodynamics

5-MT acts as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

5-HT₁, 5-HT₂, 5-HT₄, 5-HT₆, and 5-HT₇ receptors. It is an extremely potent serotonin 5-HT_2A receptor agonist ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'', with an of 0.503nM. This was more potent than any other tryptamine evaluated in two large series of compounds. For comparison,

had an of 3.87nM (7.7-fold lower) and

dimethyltryptamine Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...

(DMT) had an of 38.3nM (76-fold lower). 5-MT has been said to be 25- and 400-fold selective for the serotonin 5-HT_2B receptor over the serotonin 5-HT_2A and 5-HT_2C receptors, respectively. 5-MT, in contrast to the closely related

, has no

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

melatonin receptor Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other ...

s. However, it may 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 A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

compared to

and serotonin.

Effects in animals and humans

5-MT dose-dependently induces the

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

, a behavioral proxy of

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

effects, in rodents, and this effect is reversed by serotonin 5-HT_2A receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. As such, it may be a

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

in humans. 5-MT is only briefly mentioned in several places in

Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...

TiHKAL ''TiHKAL: The Continuation'' is a 1997 book written by Alexander Shulgin and Ann Shulgin about a family of psychoactive drugs known as tryptamines. A sequel to '' PiHKAL: A Chemical Love Story'', ''TiHKAL'' is an acronym that stands for "Trypt ...

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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and enter the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

with

peripheral administration In pharmacology and toxicology, a route of administration is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

in animals. However, it has also been reported that 5-MT shows strong peripheral selectivity in animals comparable to

and

bufotenin Bufotenin, also known as dimethylserotonin or as 5-hydroxy-''N'',''N''-dimethyltryptamine (5-HO-DMT), is a serotonergic psychedelic of the tryptamine family. It is a derivative of the psychedelic dimethyltryptamine (DMT) and of the neurotransmi ...

and that its capacity to exert central effects is limited.

Metabolism

5-MT is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalysis, catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver; however, it can also occur in the kidney. In s ...

(MAO), specifically

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

(MAO-A) and to a much lesser extent by

monoamine oxidase B Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyzes ...

(MAO-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 Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espec ...

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

. Similarly, levels of

and

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

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 The conditioned avoidance response (CAR) test, also known as the active avoidance test, is an animal test used to identify drugs with antipsychotic-like effects. It is most commonly employed as a two-way active avoidance test with rodents. The t ...

, are markedly enhanced by MAOIs, including by the dual MAO-A and MAO-B inhibitor

iproniazid Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible inhibition, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine (antidepressant), hydrazine class. It is a xenobiotic that was origi ...

and by clorgyline and selegiline. Similarly to rat findings,

levels of

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

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 In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...

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 Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used a ...

has been frequently used to potentiate the effects of 5-MT in

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

. 5-MT is orally inactive in humans presumably due to rapid metabolism by MAO-A.

Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of 5-MT include 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol. It may also be metabolized into

Chemistry

5-MT, also known as 5-methoxytryptamine or as 5-hydroxytrypamine ''O''-methyl ether, is a

substituted tryptamine Substituted tryptamines, or simply tryptamines, also known as serotonin analogues (i.e., 5-hydroxytryptamine analogues), are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all trypt ...

and a

(5-hydroxytryptamine) and precursor of

(''N''-acetyl-5-methoxytryptamine). The predicted log P of 5-MT is 0.5 to 1.41.

Analogues and derivatives

5-MT is closely related to other 5-methoxylated tryptamines such as 5-MeO-NMT,

, 5-MeO-DPT,

5-MeO-DiPT 5-MeO-DiPT, also known as 5-methoxy-''N'',''N''-diisopropyltryptamine and sometimes as foxy methoxy or simply foxy, is a psychedelic drug of the tryptamine and 5-methoxytryptamine families. It is the 5-methoxy derivative of diisopropyltryptami ...

, 5-MeO-MiPT,

5-MeO-DALT 5-MeO-DALT, also known as ''N'',''N''-diallyl-5-methoxytryptamine, or as foxtrot, is a psychedelic drug of the substituted tryptamine, tryptamine and substituted 5-methoxytryptamine, 5-methoxytryptamine families. It was first chemical synthesis, ...

, 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. Some other notable analogues of 5-MT include

, 2-methyl-5-hydroxytryptamine, 5-benzyloxytryptamine, 5-carboxamidotryptamine, 5-methyltryptamine,

5-(nonyloxy)tryptamine 5-(Nonyloxy)tryptamine (5-NOT) is a tryptamine derivative which acts as a selective agonist at the 5-HT1B receptor. Increasing the O-alkoxy chain length in this series gives generally increasing potency and selectivity for 5-HT1B, with highest a ...

, α-methyl-5-hydroxytryptamine,

acetryptine Acetryptine (International Nonproprietary Name, INN; developmental code W-2965-A; also known as 5-acetyltryptamine or 5-AT) is a drug described as an antihypertensive agent which was never marketed. Structurally, acetryptine is a substituted tryp ...

(5-acetyltryptamine), and isamide (''N''-chloroacetyl-5-methoxytryptamine), among others.

References

External links

5-Methoxytryptamine - isomer design
{{DEFAULTSORT:Methoxytryptamine, 5- 5-HT1A agonists 5-HT2A agonists 5-HT2B agonists 5-HT2C agonists 5-HT4 agonists Human drug metabolites 5-Methoxytryptamines Peripherally selective drugs Psychedelic tryptamines Serotonin receptor agonists