Tryptoline

{{Chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 470618432 | ImageFile = Tryptoline.svg | ImageClass = skin-invert-image | ImageSize = | PIN = 2,3,4,9-Tetrahydro-1''H''-pyrido[3,4-''b'']indole | OtherNames = Noreleagnine; Tetrahydronorharman; THN; 2,3,4,9-Tetrahydro-1''H''-β-carboline; 1,2,3,4-Tetrahydro-β-carboline; Tetrahydro-β-carboline; THβC; THBC |Section1={{Chembox Identifiers | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 96979 | InChI = 1/C11H12N2/c1-2-4-10-8(3-1)9-5-6-12-7-11(9)13-10/h1-4,12-13H,5-7H2 | InChIKey = CFTOTSJVQRFXOF-UHFFFAOYAW | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 269236 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C11H12N2/c1-2-4-10-8(3-1)9-5-6-12-7-11(9)13-10/h1-4,12-13H,5-7H2 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = CFTOTSJVQRFXOF-UHFFFAOYSA-N | CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 16502-01-5 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 65027TMI0H | PubChem = 107838 | SMILES = c1ccc2c(c1)c3c([nH]2)CNCC3 }} |Section2={{Chembox Properties | Formula = C₁₁H₁₂N₂ | MolarMass = 172.226 g/mol | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}

'''Tryptoline''', also known as '''1,2,3,4-tetrahydro-β-carboline''' ('''THβC''') and '''tetrahydronorharmane''' ('''THN'''), is a natural organic derivative of β-carboline.<ref name="TiHKAL" /> It is an alkaloid chemically related to tryptamines.<ref name="TiHKAL" /> Derivatives of tryptoline have a variety of pharmacological properties and are known collectively as '''tryptolines'''.<ref name="pubchem">{{cite web |title=Tryptoline |url=https://pubchem.ncbi.nlm.nih.gov/compound/107838 |website=pubchem.ncbi.nlm.nih.gov}}</ref>

==Use and effects== The properties and effects of tryptoline in humans do not appear to be known.<ref name="TiHKAL">{{CiteTiHKAL}} 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."</ref>

==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{{nbsp}}nM and 1,500{{nbsp}}nM, respectively.<ref name="NBH.Youdim1981">{{cite journal |last1=Youdim |first1=N.B.H. |last2=Oppenheim |first2=B. |title=The effect of tryptolines (1, 2, 3, 4-tetrahydro-β-carbolines) on monoamine metabolism and the platelet aggregation response in human platelets |journal=Neuroscience |date=April 1981 |volume=6 |issue=4 |pages=801–810 |doi=10.1016/0306-4522(81)90163-9 |pmid=7242917 |s2cid=37681465 |url=https://doi.org/10.1016/0306-4522(81)90163-9|url-access=subscription }}</ref>

Tryptolines are also potent reuptake inhibitors of serotonin and epinephrine, with a significantly greater selectivity for serotonin.<ref name="NBH.Youdim1981" /><ref name="RommelspacherStraussCohnitz1978">{{cite journal | vauthors = Rommelspacher H, Strauss S, Cohnitz CH | title = Inhibition of 5-hydroxytryptamine uptake by tetrahydronorharmane in vivo | journal = Naunyn Schmiedebergs Arch Pharmacol | volume = 303 | issue = 3 | pages = 229–233 | date = July 1978 | pmid = 150545 | doi = 10.1007/BF00498048 | url = }}</ref>

''In-vivo'' formation of tryptolines has been a matter of controversy.<ref name="NBH.Youdim1981" /><ref name="TiHKAL" />

Tryptoline shows weak affinity for the serotonin 5-HT_1A and 5-HT_2A receptors (K_i = 2,510{{nbsp}}nM and 3,900{{nbsp}}nM, respectively).<ref name="BojarskiCegłaCharakchieva-Minol1993" /> However, it showed a high affinity (K_i) of 28{{nbsp}}nM against tryptamine-labeled binding sites, whereas affinity for serotonin- and spiperone-labeled sites were much lower (K_i = 6,030{{nbsp}}nM and 12,030{{nbsp}}nM, respectively).<ref name="TaylorNikamWeck1987">{{cite journal | vauthors = Taylor EW, Nikam S, Weck B, Martin A, Nelson D | title = Relative selectivity of some conformationally constrained tryptamine analogs at 5-HT1, 5-HT1A and 5-HT2 recognition sites | journal = Life Sci | volume = 41 | issue = 16 | pages = 1961–1969 | date = October 1987 | pmid = 3657392 | doi = 10.1016/0024-3205(87)90749-1 | url = }}</ref><ref name="CascioKellar1982">{{cite journal | vauthors = Cascio CS, Kellar KJ | title = Tetrahydro-beta-carbolines: affinities for tryptamine and serotonergic binding sites | journal = Neuropharmacology | volume = 21 | issue = 11 | pages = 1219–1221 | date = November 1982 | pmid = 7177348 | doi = 10.1016/0028-3908(82)90185-x | url = }}</ref> The drug shows substantially lower affinity for serotonin receptors than tryptamine.<ref name="TaylorNikamWeck1987" /><ref name="CascioKellar1982" /> Tryptoline is 60-fold more potent in terms of tryptamine binding site interaction than its serotonin reuptake inhibition.<ref name="CascioKellar1982" /> The drug is inactive as an agonist of the serotonin 5-HT_2B receptor in the rat fundus stomach strip (K_B = >3,000{{nbsp}}nM).<ref name="AudiaEvrardMurdoch1996">{{cite journal | vauthors = Audia JE, Evrard DA, Murdoch GR, Droste JJ, Nissen JS, Schenck KW, Fludzinski P, Lucaites VL, Nelson DL, Cohen ML | title = Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus | journal = J Med Chem | volume = 39 | issue = 14 | pages = 2773–2780 | date = July 1996 | pmid = 8709108 | doi = 10.1021/jm960062t | url = }}</ref>

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.<ref name="CascioKellar1982" /><ref name="RommelspacherKauffmannCohnitz1977">{{cite journal | vauthors = Rommelspacher H, Kauffmann H, Cohnitz CH, Coper H | title = Pharmacological properties of tetrahydronorharmane (tryptoline) | journal = Naunyn Schmiedebergs Arch Pharmacol | volume = 298 | issue = 2 | pages = 83–91 | date = June 1977 | pmid = 560635 | doi = 10.1007/BF00508615 | url = }}</ref>

==Chemistry== ===Derivatives=== Tryptoline derivatives have been found to interact with serotonin receptors, such as the serotonin 5-HT_1A and 5-HT₂ receptors.<ref name="BojarskiCegłaCharakchieva-Minol1993">{{cite journal | vauthors = Bojarski AJ, Cegła MT, Charakchieva-Minol S, Mokrosz MJ, Maćkowiak M, Misztal S, Mokrosz JL | title = 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 | journal = Pharmazie | volume = 48 | issue = 4 | pages = 289–294 | date = April 1993 | pmid = 8321880 | doi = | url = https://web.archive.org/web/20260404220751/https://www.researchgate.net/profile/Marek-Cegla-2/publication/14877180_Structure-activity_relationship_studies_of_CNS_agents_Part_9_5-HT1A_and_5-HT2_receptor_affinity_of_some_2-_and_3-substituted_1234-tetrahydro-b-carbolines/links/5538ce710cf2239f4e79ba51/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-b-carbolines.pdf}}</ref><ref name="OrrCaoWang2022">{{cite journal | vauthors = Orr MJ, Cao AB, Wang CT, Gaisin A, Csakai A, Friswold AP, Meltzer HY, McCorvy JD, Scheidt KA | title = Discovery of Highly Potent Serotonin 5-HT2 Receptor Agonists Inspired by Heteroyohimbine Natural Products | journal = ACS Med Chem Lett | volume = 13 | issue = 4 | pages = 648–657 | date = April 2022 | pmid = 35450369 | pmc = 9014500 | doi = 10.1021/acsmedchemlett.1c00694 | url = }}</ref><ref name="CascioKellar1982" /><ref name="TaylorNikamWeck1987" /> 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-HT_2A receptor.<ref name="OrrCaoWang2022" />

==See also== * Substituted β-carboline * Norharmane * Harmane * β-Carboline * Harmala alkaloid

==References== {{Reflist}}

{{Serotonin receptor modulators}} {{Monoamine metabolism modulators}} {{Tryptamines}}

Category:N-Monoalkyltryptamines Category:Monoamine oxidase inhibitors Category:Serotonin receptor modulators Category:Tryptamine alkaloids Category:Tryptolines