Tryptoline

Tryptoline
Clinical data
Other namesNoreleagnine; Tetrahydronorharman; THN; 2,3,4,9-Tetrahydro-1H-β-carboline; 1,2,3,4-Tetrahydro-β-carboline; Tetrahydro-β-carboline; THβC; THBC
ATC code
  • None
Identifiers
  • 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.156.194 Edit this at Wikidata
Chemical and physical data
FormulaC11H12N2
Molar mass172.231 g·mol−1
3D model (JSmol)
  • c1ccc2c(c1)c3c([nH]2)CNCC3
  • InChI=1S/C11H12N2/c1-2-4-10-8(3-1)9-5-6-12-7-11(9)13-10/h1-4,12-13H,5-7H2 checkY
  • Key:CFTOTSJVQRFXOF-UHFFFAOYSA-N checkY
 X markNcheckY (what is this?)  (verify)

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

Use and effects

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

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.

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

Tryptoline shows weak affinity for the serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors (Ki = 2,510–4,310 nM, 3,040–3,900 nM, and >10,000 nM, respectively). 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). The drug shows substantially lower affinity for serotonin receptors than tryptamine. Tryptoline is 60-fold more potent in terms of tryptamine binding site interaction than its serotonin reuptake inhibition. The drug is inactive as an agonist of the serotonin 5-HT2B receptor in the rat fundus stomach strip (KB = >3,000 nM).

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.

Both tryptoline and pinoline partially substitute for the psychedelic drug LSD in rodent drug discrimination tests. The substitution by tryptoline was found to be blocked by the serotonin receptor antagonist pizotifen and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). In subsequent studies, tryptoline was used as the training drug, and fenfluramine and MDMA fully substituted for tryptoline while LSD and yohimbine partially substituted for tryptoline. Tryptoline likewise substituted for fenfluramine. In a later study, tryptoline failed to substitute for LSD, contradicting previous findings. The non-selective serotonin receptor agonists TFMPP and mCPP fully substituted for tryptoline, whereas serotonin 5-HT1A receptor agonists did not. Neither of the serotonin receptor antagonists pirenperone or metergoline antagonized the tryptoline-mediated discriminative stimulus. It was theorized that the tryptoline cue was mediated by serotonin 5-HT1B receptor activation.

In-vivo formation of tryptolines has been a matter of controversy.

Chemistry

Derivatives

Tryptoline derivatives have been found to interact with serotonin receptors, such as the serotonin 5-HT1A and 5-HT2 receptors. 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. Pinoline (6-methoxytryptoline) is another notable tryptoline derivative, acting as a weak serotonin 5-HT2A receptor agonist and as a potent serotonin 5-HT2C receptor agonist among other actions.

See also

References

  1. 1 2 3 4 Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. "Tetrahydro-β-carboline". 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. U.S. National Library of Medicine.
  3. 1 2 3 Youdim MB, Oppenheim B (1981). "The effect of tryptolines (1, 2, 3, 4-tetrahydro-beta-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-Schmiedeberg's Archives of Pharmacology. 303 (3): 229–233. doi:10.1007/BF00498048. PMID 150545.
  5. ↑ Glennon RA, Dukat M, Grella B, Hong S, Costantino L, Teitler M, et al. (August 2000). "Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors". Drug and Alcohol Dependence. 60 (2): 121–132. doi:10.1016/s0376-8716(99)00148-9. hdl:11380/17721. PMID 10940539.
  6. 1 2 Bojarski AJ, Cegła MT, Charakchieva-Minol S, Mokrosz MJ, Maćkowiak M, Misztal S, et al. (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). Die Pharmazie. 48 (4): 289–294. PMID 8321880. Archived from the original on 2026-04-04. Retrieved 2026-04-04.{{cite journal}}: CS1 maint: bot: original URL status unknown (link)
  7. 1 2 3 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 Sciences. 41 (16): 1961–1969. doi:10.1016/0024-3205(87)90749-1. PMID 3657392.
  8. 1 2 3 4 5 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.
  9. ↑ Audia JE, Evrard DA, Murdoch GR, Droste JJ, Nissen JS, Schenck KW, et al. (July 1996). "Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus". Journal of Medicinal Chemistry. 39 (14): 2773–2780. doi:10.1021/jm960062t. PMID 8709108.
  10. ↑ Rommelspacher H, Kauffmann H, Cohnitz CH, Coper H (June 1977). "Pharmacological properties of tetrahydronorharmane (tryptoline)". Naunyn-Schmiedeberg's Archives of Pharmacology. 298 (2): 83–91. doi:10.1007/BF00508615. PMID 560635.
  11. 1 2 Nielsen EB, White FJ, Holohean AM, Callahan PM, Appel JB (November 1982). "Behavioral and biochemical evidence for serotonergic actions of tetrahydro-beta-carbolines". Life Sciences. 31 (22): 2433–2439. doi:10.1016/0024-3205(82)90747-0. PMID 7154844.
  12. ↑ Schechter MD (May 1986). "Serotonergic mediation of tetrahydro-beta-carboline". Pharmacology, Biochemistry, and Behavior. 24 (5): 1209–1213. doi:10.1016/0091-3057(86)90172-3. PMID 3725827.
  13. ↑ Schechter MD (June 1986). "Discriminative profile of MDMA". Pharmacology, Biochemistry, and Behavior. 24 (6): 1533–1537. doi:10.1016/0091-3057(86)90480-6. PMID 2874566.
  14. 1 2 3 4 5 Schechter MD (September 1987). "Tetrahydro-beta-carboline may produce its stimulus effects via 5HT1B receptors". Pharmacology, Biochemistry, and Behavior. 28 (1): 1–6. doi:10.1016/0091-3057(87)90002-5. PMID 3659099.
  15. ↑ Helsley S, Fiorella D, Rabin RA, Winter JC (May 1998). "A comparison of N,N-dimethyltryptamine, harmaline, and selected congeners in rats trained with LSD as a discriminative stimulus". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 22 (4): 649–663. doi:10.1016/s0278-5846(98)00031-1. PMID 9682278.
  16. ↑ Leidenheimer NJ, Schechter MD (March 1991). "Inverse agonist properties of the THBC discriminative stimulus: asymmetrical generalization with FG 7142". Pharmacology, Biochemistry, and Behavior. 38 (3): 519–525. doi:10.1016/0091-3057(91)90007-o. PMID 1648746.
  17. 1 2 Orr MJ, Cao AB, Wang CT, Gaisin A, Csakai A, Friswold AP, et al. (April 2022). "Discovery of Highly Potent Serotonin 5-HT2 Receptor Agonists Inspired by Heteroyohimbine Natural Products". ACS Medicinal Chemistry Letters. 13 (4): 648–657. doi:10.1021/acsmedchemlett.1c00694. PMC 9014500. PMID 35450369.
  18. ↑ de la Fuente Revenga M, Pérez C, Morales-García JA, Alonso-Gil S, Pérez-Castillo A, Caignard DH, et al. (May 2015). "Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin-Pinoline Hybrids". ACS Chemical Neuroscience. 6 (5): 800–810. doi:10.1021/acschemneuro.5b00041. hdl:10261/117673. PMID 25815906.