5-Hydroxytryptophan

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5-Hydroxytryptophan
5-Hydroxy-L-Tryptophan (5-HTP).svg
5-Hydroxy-L-tryptophan-3D-balls.png
Names
IUPAC name
2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid
Other names
5-HTP; Oxitriptan
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.022.193 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH 5-Hydroxytryptophan
PubChem CID
UNII
  • InChI=1S/C11H12N2O3/c12-9(11(15)16)3-6-5-13-10-2-1-7(14)4-8(6)10/h1-2,4-5,9,13-14H,3,12H2,(H,15,16)/t9-/m0/s1 Yes check.svgY
    Key: LDCYZAJDBXYCGN-VIFPVBQESA-N Yes check.svgY
  • InChI=1/C11H12N2O3/c12-9(11(15)16)3-6-5-13-10-2-1-7(14)4-8(6)10/h1-2,4-5,9,13-14H,3,12H2,(H,15,16)/t9-/m0/s1
    Key: LDCYZAJDBXYCGN-VIFPVBQEBZ
  • O=C(O)[C@@H](N)Cc2c1cc(O)ccc1[nH]c2
Properties
C11H12N2O3
Molar mass 220.228 g·mol−1
Density 1.484 g/mL
Melting point 298 to 300 °C (568 to 572 °F; 571 to 573 K)
Boiling point 520.6 °C (969.1 °F; 793.8 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.

Contents

5-HTP can be manufactured and used as a drug and supplement with the INN Tooltip International Nonproprietary Name oxitriptan . Brand names include Cincofarm, Levothym, Levotonine, Oxyfan, Telesol, Tript-OH, and Triptum. As a drug, it is used in the treatment of depression and for certain other indications.

Production

5-HTP is produced from the amino acid tryptophan through the action of the enzyme tryptophan hydroxylase. Tryptophan hydroxylase is one of the biopterin-dependent aromatic amino acid hydroxylases. Production of 5-HTP is the rate-limiting step in 5-HT (serotonin) synthesis. 5-HTP is normally rapidly converted to 5-HT by amino acid decarboxylase. [1]

Metabolism

5-HTP is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by the enzyme aromatic-L-amino-acid decarboxylase with the help of vitamin B6. [2] This reaction occurs both in nervous tissue and in the liver. [3] 5-HTP crosses the blood–brain barrier, [4] while 5-HT does not. Excess 5-HTP, especially when administered with vitamin B6, is thought to be metabolized and excreted. [5] [6]

Metabolic pathway from tryptophan to serotonin. Trp-5ht-pathway.svg
Metabolic pathway from tryptophan to serotonin.


5-HTP AAAD Serotonin
5-Hydroxy-L-Tryptophan (5-HTP).svg   Serotonin (5-HT).svg
PLP
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Dietary sources

Though 5-HTP is found in food only in insignificant quantities, it is a chemical involved intermediately in the metabolism of tryptophan, an amino acid found in all unfractionated foods, with lower total amino acid content correlating with increased tryptophan absorption. [7]

Use as a medication and supplement

5-HTP is used medically and as a supplement under the name oxitriptan in the treatment of depression and for certain other indications.

It can be potentiated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor such as carbidopa or benserazide. These agents increase the strength and duration of oxitriptan. An investigational combination formulation is oxitriptan/carbidopa.

Research

Psychedelic effects

5-HTP robustly produces the head-twitch response (HTR) in rodents when administered at relatively high doses. [8] [9] [10] [11] Similarly, intracerebroventricular injection of serotonin, but not peripheral administration of serotonin, produces the HTR. [9] [8] [11] The HTR is induced by serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin and is a behavioral proxy of psychedelic effects. [12] [8]

The HTR of 5-HTP is blocked by serotonin 5-HT2A receptor antagonists, which block the hallucinogenic effects of serotonergic psychedelics in humans, is prevented by aromatic L-amino acid decarboxylase (AAAD) inhibitors, which block conversion of 5-HTP into serotonin, and is potentiated by monoamine oxidase A (MAO-A) inhibitors, which prevent the degradation of serotonin and other endogenous tryptamines. [9] [8] [10] [11] In addition, the HTR of 5-HTP is abolished by indolethylamine N-methyltransferase (INMT) inhibitors, which block conversion of serotonin and other endogenous tryptamines into N-methylated tryptamines, such as N-methylserotonin (NMS; norbufotenin), bufotenin (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT), and N,N-dimethyltryptamine (DMT). [8] [13] [11] These N-methylated tryptamines are well-known for their psychedelic effects, whereas serotonin itself, without biotransformation, does not seem to produce psychedelic effects. [8] [11] 5-HTP has not been found to produce psychedelic effects in humans, which has been attributed to the high doses required to produce such effects. [8] [10] The 5-HTP doses that produce the HTR in rodents are orders of magnitude higher than the doses of 5-HTP that have been used safely and therapeutically in humans. [10]

The lack of the HTR and psychedelic effects with serotonin itself has been attributed to the fact that these effects appear to be dependent on activation of a population of intracellular 5-HT2A receptors expressed in cortical neurons in the medial prefrontal cortex (mPFC) that lack the serotonin transporter (SERT) and are inaccessible to serotonin. [14] [15] Serotonin itself is too hydrophilic to enter serotonergic neurons without the SERT, whereas serotonergic psychedelics and serotonin's N-methylated metabolites and analogues are lipophilic and readily enter these neurons. [14] [15] These findings may also explain why selective serotonin reuptake inhibitors (SSRIs) and related serotonergic agents do not produce psychedelic effects. [14]

Related Research Articles

<span class="mw-page-title-main">Serotonin</span> Monoamine neurotransmitter

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex, touching on diverse functions including mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction.

<span class="mw-page-title-main">Tryptophan</span> Chemical compound

Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic beta carbon substituent. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3 (niacin). It is encoded by the codon UGG.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

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. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

<span class="mw-page-title-main">Benserazide</span> Chemical compound often used as medication

Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

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, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<span class="mw-page-title-main">Tryptophan hydroxylase</span> Class of enzymes

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aromatic amino acid hydroxylases. TPH catalyzes the following chemical reaction

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<span class="mw-page-title-main">TPH1</span> Protein-coding gene in the species Homo sapiens

Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1 gene.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

<span class="mw-page-title-main">Oxitriptan</span> OTC medication for depression

Oxitriptan, also known as L-5-hydroxytryptophan (5-HTP) and sold under various brand names, is a medication and over-the-counter dietary supplement used in the treatment of depression and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Substituted tryptamine</span> Class of indoles

Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.

<span class="mw-page-title-main">Head-twitch response</span> Head movement in rodants upon 5-HT2A receptor activation

The head-twitch response (HTR) is a rapid side-to-side head movement that occurs in mice and rats after the serotonin 5-HT2A receptor is activated. The prefrontal cortex may be the neuroanatomical locus mediating the HTR. Many serotonergic hallucinogens, including lysergic acid diethylamide (LSD), induce the head-twitch response, and so the HTR is used as a behavioral model of hallucinogen effects. However while there is generally a good correlation between compounds that induce head twitch in mice and compounds that are hallucinogenic in humans, it is unclear whether the head twitch response is primarily caused by 5-HT2A receptors, 5-HT2C receptors or both, though recent evidence shows that the HTR is mediated by the 5-HT2A receptor and modulated by the 5-HT2C receptor. Also, the effect can be non-specific, with head twitch responses also produced by some drugs that do not act through 5-HT2 receptors, such as phencyclidine, yohimbine, atropine and cannabinoid receptor antagonists. As well, compounds such as 5-HTP, fenfluramine, 1-Methylpsilocin, Ergometrine, and 3,4-di-methoxyphenethylamine (DMPEA) can also produce head twitch and do stimulate serotonin receptors, but are not hallucinogenic in humans. This means that while the head twitch response can be a useful indicator as to whether a compound is likely to display hallucinogenic activity in humans, the induction of a head twitch response does not necessarily mean that a compound will be hallucinogenic, and caution should be exercised when interpreting such results.

<span class="mw-page-title-main">5-Chloro-αMT</span> Chemical compound

5-Chloro-α-methyltryptamine (5-Chloro-αMT), also known as PAL-542, is a tryptamine derivative related to α-methyltryptamine (αMT) and one of only a few known specific serotonin-dopamine releasing agents (SDRAs). It has been investigated in animals as a potential treatment for cocaine dependence. The EC50 values of 5-chloro-αMT in evoking the in vitro release of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in rat synaptosomes were reported as 16 nM, 54 nM, and 3434 nM, with an NE/DA ratio of 63.6 and a DA/5-HT ratio of 3.38, indicating that it is a highly specific and well-balanced SDRA. However, 5-chloro-αMT has also been found to act as a potent full agonist of the 5-HT2A receptor, with an EC50 value of 6.27 nM and an efficacy of 105%. It is likely to act as a potent agonist of other serotonin receptors as well.

<span class="mw-page-title-main">Monoamine precursor</span>

Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan are precursors of serotonin and melatonin, while the amino acids L-phenylalanine, L-tyrosine, and L-DOPA (levodopa) are precursors of dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

<span class="mw-page-title-main">Carbidopa/oxitriptan</span> Medication

Carbidopa/oxitriptan, or carbidopa/5-hydroxytryptophan (carbidopa/5-HTP), is a combination of 5-hydroxytryptophan (oxitriptan), a serotonin precursor, and carbidopa, a peripherally selective aromatic L-amino acid decarboxylase inhibitor, which is under development as an antidepressant for the treatment of depressive disorders. As of June 2020, it is in phase 1 clinical trials for this indication.

<small>L</small>-Tryptophan decarboxylase Enzyme

L-Tryptophan decarboxylase is an enzyme distinguished by the substrate L-tryptophan.

<span class="mw-page-title-main">Neurotransmitter prodrug</span> A prodrug of a neurotransmitter

A neurotransmitter prodrug, or neurotransmitter precursor, is a drug that acts as a prodrug of a neurotransmitter. A variety of neurotransmitter prodrugs have been developed and used in medicine. They can be useful when the neurotransmitter itself is not suitable for use as a pharmaceutical drug owing to unfavorable pharmacokinetic or physicochemical properties, for instance susceptibility to metabolism or lack of blood–brain barrier permeability. Besides their use in medicine, neurotransmitter prodrugs have also been used as recreational drugs in some cases.

References

  1. ↑ Turner EH, Loftis JM, Blackwell AD (March 2006). "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacology & Therapeutics. 109 (3): 325–38. doi:10.1016/j.pharmthera.2005.06.004. PMID   16023217. S2CID   2563606.
  2. ↑ Rahman MK, Nagatsu T, Sakurai T, Hori S, Abe M, Matsuda M (October 1982). "Effect of pyridoxal phosphate deficiency on aromatic L-amino acid decarboxylase activity with L-DOPA and L-5-hydroxytryptophan as substrates in rats". Japanese Journal of Pharmacology. 32 (5): 803–11. doi: 10.1254/jjp.32.803 . PMID   6983619.
  3. ↑ Bouchard S, Bousquet C, Roberge AG (September 1981). "Characteristics of dihydroxyphenylalanine/5-hydroxytryptophan decarboxylase activity in brain and liver of cat". Journal of Neurochemistry. 37 (3): 781–7. doi:10.1111/j.1471-4159.1982.tb12555.x. PMID   6974228. S2CID   43853143.
  4. ↑ Nakatani Y, Sato-Suzuki I, Tsujino N, Nakasato A, Seki Y, Fumoto M, Arita H (May 2008). "Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat". The European Journal of Neuroscience. 27 (9): 2466–72. doi:10.1111/j.1460-9568.2008.06201.x. PMID   18445233. S2CID   18940166.
  5. ↑ Bouchard S, Roberge AG (July 1979). "Biochemical properties and kinetic parameters of dihydroxyphenylalanine--5-hydroxytryptophan decarboxylase in brain, liver, and adrenals of cat". Canadian Journal of Biochemistry. 57 (7): 1014–8. doi:10.1139/o79-126. PMID   39668.
  6. ↑ Amamoto T, Sarai K (September 1976). "On the tryptophan-serotonin metabolism in manic-depressive disorders. Changes in plasma 5-HT and 5-HIAA levels and urinary 5-HIAA excretion following oral loading of L-5HTP in patients with depression". Hiroshima Journal of Medical Sciences. 25 (2–3): 135–40. PMID   1088369.
  7. ↑ "5-Hydroxytryptophan". University of Maryland Medical Center. Archived from the original on 6 January 2010. Retrieved 21 January 2010.
  8. 1 2 3 4 5 6 7 Kozlenkov, Alexey; González-Maeso, Javier (2013). "Animal Models and Hallucinogenic Drugs". The Neuroscience of Hallucinations. New York, NY: Springer New York. p. 253–277. doi:10.1007/978-1-4614-4121-2_14. ISBN   978-1-4614-4120-5.
  9. 1 2 3 Schmid, Cullen L.; Bohn, Laura M. (2018). "βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events". 5-HT2A Receptors in the Central Nervous System. Cham: Springer International Publishing. p. 31–55. doi:10.1007/978-3-319-70474-6_2. ISBN   978-3-319-70472-2.
  10. 1 2 3 4 Jaster AM, de la Fuente Revenga M, González-Maeso J (July 2022). "Molecular targets of psychedelic-induced plasticity". J Neurochem. 162 (1): 80–88. doi:10.1111/jnc.15536. PMC   9068831 . PMID   34741320.
  11. 1 2 3 4 5 Schmid CL, Bohn LM (October 2010). "Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo". J Neurosci. 30 (40): 13513–24. doi:10.1523/JNEUROSCI.1665-10.2010. PMC   3001293 . PMID   20926677.
  12. ↑ Canal CE, Morgan D (2012). "Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model". Drug Test Anal. 4 (7–8): 556–576. doi:10.1002/dta.1333. PMC   3722587 . PMID   22517680.
  13. ↑ Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". Curr Top Behav Neurosci. 36: 159–199. doi:10.1007/7854_2016_466. PMC   5787039 . PMID   28224459.
  14. 1 2 3 Sapienza, Jacopo (13 October 2023). "The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research?". Psychoactives. 2 (4): 287–293. doi: 10.3390/psychoactives2040018 . ISSN   2813-1851.
  15. 1 2 Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE (February 2023). "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". Science. 379 (6633): 700–706. doi:10.1126/science.adf0435. PMC   10108900 . PMID   36795823.
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