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Tryptoline, also known as 1,2,3,4-tetrahydro-β-carboline (THβC) and tetrahydronorharmane (THN), is a natural organic derivative of β-carboline.[1] It is an alkaloid chemically related to tryptamines.[1] Derivatives of tryptoline have a variety of pharmacological properties and are known collectively as tryptolines.[2]

Use and effects

The properties and effects of tryptoline in humans do not appear to be known.[1]

Pharmacology

Pharmacodynamics

Tryptolines are competitive selective inhibitors of the enzyme monoamine oxidase type A (MAO-A). 5-Hydroxytryptoline and 5-methoxytryptoline are the most active monoamine oxidase inhibitors (MAOIs) with IC50 values of 500 nM and 1,500 nM, respectively.[3]

Tryptolines are also potent reuptake inhibitors of serotonin and epinephrine, with a significantly greater selectivity for serotonin.[3][4]

In-vivo formation of tryptolines has been a matter of controversy.[3][1]

Tryptoline shows weak affinity for the serotonin 5-HT1A and 5-HT2A receptors (Ki = 2,510 nM and 3,900 nM, respectively).[5] However, it showed a high affinity (Ki) of 28 nM against tryptamine–labeled binding sites, whereas affinity for serotonin- and spiperone-labeled sites were much lower (Ki = 6,030 nM and 12,030 nM, respectively).[6][7] The drug shows substantially lower affinity for serotonin receptors than tryptamine.[6][7] Tryptoline is 60-fold more potent in terms of tryptamine binding site interaction than its serotonin reuptake inhibition.[7] The drug is inactive as an agonist of the serotonin 5-HT2B receptor in the rat fundus stomach strip (KB = >3,000 nM).[8]

Tryptoline is known to produce various behavioral effects in animals, including analgesia, hypothermia, and hypophagia, as well as antidopaminergic-like reversal of behavioral effects of apomorphine such as hyperlocomotion.[7][9]

Chemistry

Derivatives

Tryptoline derivatives have been found to interact with serotonin receptors, such as the serotonin 5-HT1A and 5-HT2 receptors.[5][10][7][6] A couple of notable derivatives, 1-ethyl-6-hydroxytryptoline and 1-(2,4,5-trimethoxyphenyl)-6-chlorotryptoline, are potent and high-efficacy agonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A receptor.[10]

See also

References

  1. ^ a b c d Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. https://www.erowid.org/library/books_online/tihkal/tihkal44.shtml “Tetrahydro-β-carboline (THβC, tryptoline) has also been demonstrated as being formed in the brain by the simple fusion of tryptamine with formaldehyde, from methyltetrahydrofolate, and it is a normal component of human urine. It is the structural icon of the family of tetrahydro-β-carbolines without the methyl group at the 1-position, sometimes called the “tryptolines.” It, and the 2-methyl homologue mentioned just above, are both natural metabolites of DMT. I had the lucky timing to be present at a seminar at the Department of Pharmacology, at the U.C. Medical School in San Francisco, when the crowd from Stanford came up to give the first San Francisco unveiling of the “tryptoline” word. I remember that I was not the only chemist in the audience who groaned at the use of a totally unneeded and artificial name. But these researchers did a lot of work and a lot of publishing, and the term is now pretty well established in the literature. A cautionary note is appropriate here. It is essential, in abbreviating this material as THβC that the “β” be included. Without it, the code “THC” will be assumed immediately to stand for tetrahydrocannabinol, the active component of marijuana.”
  2. ^ “Tryptoline”. pubchem.ncbi.nlm.nih.gov.
  3. ^ a b c Youdim, N.B.H.; Oppenheim, B. (April 1981). “The effect of tryptolines (1, 2, 3, 4-tetrahydro-β-carbolines) on monoamine metabolism and the platelet aggregation response in human platelets”. Neuroscience. 6 (4): 801–810. doi:10.1016/0306-4522(81)90163-9. PMID 7242917. S2CID 37681465.
  4. ^ Rommelspacher H, Strauss S, Cohnitz CH (July 1978). “Inhibition of 5-hydroxytryptamine uptake by tetrahydronorharmane in vivo”. Naunyn Schmiedebergs Arch Pharmacol. 303 (3): 229–233. doi:10.1007/BF00498048. PMID 150545.
  5. ^ a b Bojarski AJ, Cegła MT, Charakchieva-Minol S, Mokrosz MJ, Maćkowiak M, Misztal S, Mokrosz JL (April 1993). “Structure-activity relationship studies of CNS agents. Part 9: 5-HT1A and 5-HT2 receptor affinity of some 2- and 3-substituted 1,2,3,4-tetrahydro-beta-carbolines” (PDF). Pharmazie. 48 (4): 289–294. PMID 8321880.
  6. ^ a b c Taylor EW, Nikam S, Weck B, Martin A, Nelson D (October 1987). “Relative selectivity of some conformationally constrained tryptamine analogs at 5-HT1, 5-HT1A and 5-HT2 recognition sites”. Life Sci. 41 (16): 1961–1969. doi:10.1016/0024-3205(87)90749-1. PMID 3657392.
  7. ^ a b c d e Cascio CS, Kellar KJ (November 1982). “Tetrahydro-beta-carbolines: affinities for tryptamine and serotonergic binding sites”. Neuropharmacology. 21 (11): 1219–1221. doi:10.1016/0028-3908(82)90185-x. PMID 7177348.
  8. ^ Audia JE, Evrard DA, Murdoch GR, Droste JJ, Nissen JS, Schenck KW, Fludzinski P, Lucaites VL, Nelson DL, Cohen ML (July 1996). “Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus”. J Med Chem. 39 (14): 2773–2780. doi:10.1021/jm960062t. PMID 8709108.
  9. ^ Rommelspacher H, Kauffmann H, Cohnitz CH, Coper H (June 1977). “Pharmacological properties of tetrahydronorharmane (tryptoline)”. Naunyn Schmiedebergs Arch Pharmacol. 298 (2): 83–91. doi:10.1007/BF00508615. PMID 560635.
  10. ^ a b Orr MJ, Cao AB, Wang CT, Gaisin A, Csakai A, Friswold AP, Meltzer HY, McCorvy JD, Scheidt KA (April 2022). “Discovery of Highly Potent Serotonin 5-HT2 Receptor Agonists Inspired by Heteroyohimbine Natural Products”. ACS Med Chem Lett. 13 (4): 648–657. doi:10.1021/acsmedchemlett.1c00694. PMC 9014500. PMID 35450369.