1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline

{{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | drug_name = | image = 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline.svg | image_class = skin-invert-image | width = 200px | caption =

| legal_status =

| IUPAC_name = 1-(trichloromethyl)-2,3,4,9-tetrahydro-1''H''-pyrido[3,4-b]indole | C=12 | H=11 | Cl=3 | N=2 | SMILES = C1CNC(C2=C1C3=CC=CC=C3N2)C(Cl)(Cl)Cl | StdInChI = 1S/C12H11Cl3N2/c13-12(14,15)11-10-8(5-6-16-11)7-3-1-2-4-9(7)17-10/h1-4,11,16-17H,5-6H2 | StdInChIKey = DPPAKKMPHBZNQA-UHFFFAOYSA-N }}

'''1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline''' ('''1-TCMTC'''), also known as '''tryptamine–chloral''' ('''TaClo'''), is a [[mammalian]] [[alkaloid]] and [[potency (pharmacology)|potent]] [[dopaminergic neurotoxin]] of the [[substituted β-carboline|β-carboline]] family.<ref name="RiedererFoleyBringmann2002">{{cite journal | vauthors = Riederer P, Foley P, Bringmann G, Feineis D, Brückner R, Gerlach M | date = May 2002 | title = Biochemical and pharmacological characterization of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline: a biologically relevant neurotoxin? | journal = European Journal of Pharmacology | volume = 442 | issue = 1–2 | pages = 1–16 | doi = 10.1016/s0014-2999(02)01308-0 | pmid = 12020676 }}</ref><ref name="BringmannGodFeineis1995a">{{cite journal | vauthors = Bringmann G, God R, Feineis D, Wesemann W, Riederer P, Rausch WD, Reichmann H, Sontag KH | title = The TaClo concept: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a new toxin for dopaminergic neurons | journal = Journal of Neural Transmission. Supplementum | volume = 46 | issue = | pages = 235–244 | date = 1995 | pmid = 8821060 | doi = | url = }}</ref><ref name="BringmannGodFeineis1995b">{{cite journal | vauthors = Bringmann G, God R, Feineis D, Janetzky B, Reichmann H | title = TaClo as a neurotoxic lead: improved synthesis, stereochemical analysis, and inhibition of the mitochondrial respiratory chain | journal = Journal of Neural Transmission. Supplementum | volume = 46 | issue = | pages = 245–254 | date = 1995 | pmid = 8821061 | doi = | url = }}</ref><ref name="BringmannFeineisGod2002" /> It can form spontaneously ''[[in vivo]]'' as a [[condensation reaction|condensation]] [[chemical product|product]] of [[endogenous]] [[tryptamine]] (Ta) with [[chloral hydrate]] (Clo) or [[trichloroethylene]].<ref name="RiedererFoleyBringmann2002" /><ref name="BringmannGodFeineis1995a" /><ref name="BringmannGodFeineis1995b" /><ref name="JanetzkyGodBringmann1995">{{cite journal | vauthors = Janetzky B, God R, Bringmann G, Reichmann H | title = 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, a new inhibitor of complex I | journal = Journal of Neural Transmission. Supplementum | volume = 46 | issue = | pages = 265–273 | date = 1995 | pmid = 8821063 | doi = | url = }}</ref><ref name="BringmannGodFähr1999">{{cite journal | vauthors = Bringmann G, God R, Fähr S, Feineis D, Fornadi K, Fornadi F | title = Identification of the dopaminergic neurotoxin 1-trichloromethyl-1,2, 3,4-tetrahydro-beta-carboline in human blood after intake of the hypnotic chloral hydrate | journal = Analytical Biochemistry | volume = 270 | issue = 1 | pages = 167–175 | date = May 1999 | pmid = 10328779 | doi = 10.1006/abio.1999.4088 | url = }}</ref><ref name="LeuschnerBeuscherZimmermann1998" /><ref name="BringmannFeineisGod2002">{{cite journal | vauthors = Bringmann G, Feineis D, God R, Peters K, Peters EM, Scholz J, Riederer F, Moser A | title = 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: chemistry and biochemical effects on catecholamine biosynthesis | journal = Bioorganic & Medicinal Chemistry | volume = 10 | issue = 7 | pages = 2207–2214 | date = July 2002 | pmid = 11983518 | doi = 10.1016/s0968-0896(02)00060-3 | url = }}</ref><ref name="LiuShinDang2018">{{cite journal | vauthors = Liu M, Shin EJ, Dang DK, Jin CH, Lee PH, Jeong JH, Park SJ, Kim YS, Xing B, Xin T, Bing G, Kim HC | title = Trichloroethylene and Parkinson's Disease: Risk Assessment | journal = Molecular Neurobiology | volume = 55 | issue = 7 | pages = 6201–6214 | date = July 2018 | pmid = 29270919 | doi = 10.1007/s12035-017-0830-x | url = }}</ref> The drug shows structural similarity to [[MPTP]].<ref name="BringmannGodFeineis1995a" /><ref name="SontagHeimSontag1995">{{cite journal | vauthors = Sontag KH, Heim C, Sontag TA, God R, Reichmann H, Wesemann W, Rausch WD, Riederer P, Bringmann G | title = Long-term behavioural effects of TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) after subchronic treatment in rats | journal = Journal of Neural Transmission. Supplementum | volume = 46 | issue = | pages = 283–289 | date = 1995 | pmid = 8821065 | doi = | url = }}</ref><ref name="HeimSontag1997">{{cite journal | vauthors = Heim C, Sontag KH | title = The halogenated tetrahydro-beta-carboline "TaClo": a progressively-acting neurotoxin | journal = Journal of Neural Transmission. Supplementum | series = Journal of Neural Transmission. Supplementa | volume = 50 | issue = | pages = 107–111 | date = 1997 | pmid = 9120411 | doi = 10.1007/978-3-7091-6842-4_11| isbn = 978-3-211-82898-4 | url = }}</ref> As with MPTP, it acts as an inhibitor of [[mitochondrial complex I]], but shows greater [[potency (pharmacology)|potency]] in comparison.<ref name="RiedererFoleyBringmann2002" /><ref name="JanetzkyGodBringmann1995" />

TaClo has been found to acutely elevate levels of [[serotonin]] and possibly [[dopamine]] in the brain in rodents, and elevated serotonin levels may be involved in its dopaminergic neurotoxicity.<ref name="RiedererFoleyBringmann2002" /><ref name="GerlachXiaoHeim1998">{{cite journal | vauthors = Gerlach M, Xiao AY, Heim C, Lan J, God R, Feineis D, Bringmann G, Riederer P, Sontag KH | title = 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline increases extracellular serotonin and stimulates hydroxyl radical production in rats | journal = Neuroscience Letters | volume = 257 | issue = 1 | pages = 17–20 | date = November 1998 | pmid = 9857955 | doi = 10.1016/s0304-3940(98)00791-5 | url = }}</ref> It exclusively enters [[serotonin|serotonergic]] [[neuron]]s via [[passive diffusion]] rather than by the [[serotonin transporter]] (SERT).<ref name="RiedererFoleyBringmann2002" /><ref name="BringmannBrücknerMössner2000">{{cite journal | vauthors = Bringmann G, Brückner R, Mössner R, Feineis D, Heils A, Lesch KP | title = Effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) on human serotonergic cells | journal = Neurochemical Research | volume = 25 | issue = 6 | pages = 837–843 | date = June 2000 | pmid = 10944002 | doi = 10.1023/a:1007521625088 | url = }}</ref> TaClo produces long-lasting behavioral changes in rodents, such as [[parkinsonism]], changes in [[locomotor activity]], and altered sensitivity to [[dopaminergic drug]]s.<ref name="RiedererFoleyBringmann2002" /><ref name="SontagHeimSontag1995" /><ref name="HeimSontag1997" /><ref name="LeuschnerBeuscherZimmermann1998">{{cite journal | vauthors = Leuschner J, Beuscher N, Zimmermann T, Schürer M, Schulz HU, Jeromin J, Ritter H | title = Untersuchungen zu Plasmaspiegeln des Neurotoxins 1-Trichlormethyl-1,2,3,4-tetrahydro-beta-carbolin (TaClo) beim Menschen nach oraler Verabreichung von Chloralhydrat | trans-title = The plasma level of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) in man after oral administration of chloral hydrate | language = German | journal = Arzneimittelforschung | volume = 48 | issue = 1 | pages = 1–5 | date = January 1998 | pmid = 9522023 | doi = | url = }}</ref> While initially characterized as a dopaminergic neurotoxin, TaClo has since been reported to be non-selective, acting as a general strong [[cytotoxin]] and without specificity for dopaminergic neurons nor for [[neuron]]s generally.<ref name="StorchHwangBringmann2006">{{cite journal | vauthors = Storch A, Hwang YI, Bringmann G, Feineis D, Ott S, Brückner R, Schwarz J | title = Cytotoxicity of chloral-derived beta-carbolines is not specific towards neuronal nor dopaminergic cells | journal = Journal of Neural Transmission | volume = 113 | issue = 12 | pages = 1895–1901 | date = December 2006 | pmid = 16868795 | doi = 10.1007/s00702-006-0495-5 | url = }}</ref>

The [[chemical synthesis]] of TaClo has been described.<ref name="RiedererFoleyBringmann2002" /><ref name="BringmannHille1990" /><ref name="BringmannGodFeineis1995b" /> The ''N''-[[methyl group|methyl]] [[chemical derivative|derivative]] of TaClo, [[N-methyl-TaClo|''N''-methyl-TaClo]], is a more potent dopaminergic neurotoxin than TaClo.<ref name="RiedererFoleyBringmann2002" /><ref name="JanetzkyGodBringmann1995" /><ref name="GroteClementWesemann1995">{{cite journal | vauthors = Grote C, Clement HW, Wesemann W, Bringmann G, Feineis D, Riederer P, Sontag KH | title = Biochemical lesions of the nigrostriatal system by TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) and derivatives | journal = Journal of Neural Transmission. Supplementum | volume = 46 | issue = | pages = 275–281 | date = 1995 | pmid = 8821064 | doi = | url = }}</ref> Another [[structural analog|analogue]], [[TaBro]], is also more potent.<ref name="RiedererFoleyBringmann2002" /><ref name="GroteClementWesemann1995" /> Other analogues have been described as well.<ref name="RiedererFoleyBringmann2002" /><ref name="BringmannBrücknerMössner2000" /><ref name="BringmannMünchbachFeineis2001">{{cite journal | vauthors = Bringmann G, Münchbach M, Feineis D, Faulhaber K, Ihmels H | date = May 2001 | title = Studies on single-strand scissions to cell-free plasmid DNA by the dopaminergic neurotoxin 'TaClo' (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) | journal = Neuroscience Letters | volume = 304 | issue = 1–2 | pages = 41–44 | doi = 10.1016/s0304-3940(01)01731-1 | pmid = 11335050 }}</ref>

TaClo was first described in the [[scientific literature]] in 1990.<ref name="BringmannHille1990">{{cite journal | vauthors = Bringmann G, Hille A | title = Endogenous alkaloids in man, VII: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline--a potential chloral-derived indol alkaloid in man | journal = Archiv der Pharmazie | volume = 323 | issue = 9 | pages = 567–569 | date = September 1990 | pmid = 2288478 | doi = 10.1002/ardp.19903230903 | url = }}</ref> It was subsequently described as a [[neurotoxin]] in 1995.<ref name="BringmannGodFeineis1995a" /><ref name="BringmannGodFeineis1995b" /> The compound may be an endogenous or environmental neurotoxin and might be involved in the development of [[Parkinson's disease]] in some people.<ref name="RiedererFoleyBringmann2002" /><ref name="KochenKohlmüllerBiasi2003">{{cite book | vauthors = Kochen W, Kohlmüller D, De Biasi P, Ramsay R | title = The endogeneous formation of highly chlorinated tetrahydro-beta-carbolines as a possible causative mechanism in idiopathic Parkinson's disease | chapter = The Endogeneous Formation of Highly Chlorinated Tetrahydro-ß-Carbolines as a Possible Causative Mechanism in Idiopathic Parkinson's Disease | series = Advances in Experimental Medicine and Biology | volume = 527 | pages = 253–263 | date = 2003 | pmid = 15206739 | doi = 10.1007/978-1-4615-0135-0_29 | isbn = 978-1-4613-4939-6 | url = }}</ref><ref name="LiuShinDang2018" />

== See also == * [[Substituted β-carboline]] * [[Monoamine neurotoxin]]

== References == {{Reflist}}

[[Category:Human drug metabolites]] [[Category:Monoaminergic neurotoxins]] [[Category:Trichloromethyl compounds]] [[Category:Tryptolines]] [[Category:Beta-Carbolines]]