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

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline
Clinical data
Other namesTaClo; 1-Trichloromethyl-THβC; 1-TCMTC
ATC code
  • None
Identifiers
  • 1-(trichloromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H11Cl3N2
Molar mass289.58 g·mol−1
3D model (JSmol)
  • C1CNC(C2=C1C3=CC=CC=C3N2)C(Cl)(Cl)Cl
  • InChI=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
  • Key: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 potent dopaminergic neurotoxin of the β-carboline family.[1][2][3][4] It can form spontaneously in vivo as a condensation product of endogenous tryptamine (Ta) with chloral hydrate (Clo) or trichloroethylene.[1][2][3][5][6][7][4][8] The drug shows structural similarity to MPTP.[2][9][10] As with MPTP, it acts as an inhibitor of mitochondrial complex I, but shows greater potency in comparison.[1][5]

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.[1][11] It exclusively enters serotonergic neurons via passive diffusion rather than by the serotonin transporter (SERT).[1][12] TaClo produces long-lasting behavioral changes in rodents, such as parkinsonism, changes in locomotor activity, and altered sensitivity to dopaminergic drugs.[1][9][10][7] 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 neurons generally.[13]

The chemical synthesis of TaClo has been described.[1][14][3] The N-methyl derivative of TaClo, N-methyl-TaClo, is a more potent dopaminergic neurotoxin than TaClo.[1][5][15] Another analogue, TaBro, is also more potent.[1][15] Other analogues have been described as well.[1][12][16]

TaClo was first described in the scientific literature in 1990.[14] It was subsequently described as a neurotoxin in 1995.[2][3] The compound may be an endogenous or environmental neurotoxin and might be involved in the development of Parkinson's disease in some people.[1][17][8]

See also

References

  1. ^ a b c d e f g h i j k Riederer P, Foley P, Bringmann G, Feineis D, Brückner R, Gerlach M (May 2002). "Biochemical and pharmacological characterization of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline: a biologically relevant neurotoxin?". European Journal of Pharmacology. 442 (1–2): 1–16. doi:10.1016/s0014-2999(02)01308-0. PMID 12020676.
  2. ^ a b c d Bringmann G, God R, Feineis D, Wesemann W, Riederer P, Rausch WD, et al. (1995). "The TaClo concept: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a new toxin for dopaminergic neurons". Journal of Neural Transmission. Supplementum. 46: 235–244. PMID 8821060.
  3. ^ a b c d Bringmann G, God R, Feineis D, Janetzky B, Reichmann H (1995). "TaClo as a neurotoxic lead: improved synthesis, stereochemical analysis, and inhibition of the mitochondrial respiratory chain". Journal of Neural Transmission. Supplementum. 46: 245–254. PMID 8821061.
  4. ^ a b Bringmann G, Feineis D, God R, Peters K, Peters EM, Scholz J, et al. (July 2002). "1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: chemistry and biochemical effects on catecholamine biosynthesis". Bioorganic & Medicinal Chemistry. 10 (7): 2207–2214. doi:10.1016/s0968-0896(02)00060-3. PMID 11983518.
  5. ^ a b c Janetzky B, God R, Bringmann G, Reichmann H (1995). "1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, a new inhibitor of complex I". Journal of Neural Transmission. Supplementum. 46: 265–273. PMID 8821063.
  6. ^ Bringmann G, God R, Fähr S, Feineis D, Fornadi K, Fornadi F (May 1999). "Identification of the dopaminergic neurotoxin 1-trichloromethyl-1,2, 3,4-tetrahydro-beta-carboline in human blood after intake of the hypnotic chloral hydrate". Analytical Biochemistry. 270 (1): 167–175. doi:10.1006/abio.1999.4088. PMID 10328779.
  7. ^ a b Leuschner J, Beuscher N, Zimmermann T, Schürer M, Schulz HU, Jeromin J, et al. (January 1998). "Untersuchungen zu Plasmaspiegeln des Neurotoxins 1-Trichlormethyl-1,2,3,4-tetrahydro-beta-carbolin (TaClo) beim Menschen nach oraler Verabreichung von Chloralhydrat" [The plasma level of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) in man after oral administration of chloral hydrate]. Arzneimittelforschung (in German). 48 (1): 1–5. PMID 9522023.
  8. ^ a b Liu M, Shin EJ, Dang DK, Jin CH, Lee PH, Jeong JH, et al. (July 2018). "Trichloroethylene and Parkinson's Disease: Risk Assessment". Molecular Neurobiology. 55 (7): 6201–6214. doi:10.1007/s12035-017-0830-x. PMID 29270919.
  9. ^ a b Sontag KH, Heim C, Sontag TA, God R, Reichmann H, Wesemann W, et al. (1995). "Long-term behavioural effects of TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) after subchronic treatment in rats". Journal of Neural Transmission. Supplementum. 46: 283–289. PMID 8821065.
  10. ^ a b Heim C, Sontag KH (1997). "The halogenated tetrahydro-beta-carboline "TaClo": a progressively-acting neurotoxin". Journal of Neural Transmission. Supplementum. Journal of Neural Transmission. Supplementa. 50: 107–111. doi:10.1007/978-3-7091-6842-4_11. ISBN 978-3-211-82898-4. PMID 9120411.
  11. ^ Gerlach M, Xiao AY, Heim C, Lan J, God R, Feineis D, et al. (November 1998). "1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline increases extracellular serotonin and stimulates hydroxyl radical production in rats". Neuroscience Letters. 257 (1): 17–20. doi:10.1016/s0304-3940(98)00791-5. PMID 9857955.
  12. ^ a b Bringmann G, Brückner R, Mössner R, Feineis D, Heils A, Lesch KP (June 2000). "Effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) on human serotonergic cells". Neurochemical Research. 25 (6): 837–843. doi:10.1023/a:1007521625088. PMID 10944002.
  13. ^ Storch A, Hwang YI, Bringmann G, Feineis D, Ott S, Brückner R, et al. (December 2006). "Cytotoxicity of chloral-derived beta-carbolines is not specific towards neuronal nor dopaminergic cells". Journal of Neural Transmission. 113 (12): 1895–1901. doi:10.1007/s00702-006-0495-5. PMID 16868795.
  14. ^ a b Bringmann G, Hille A (September 1990). "Endogenous alkaloids in man, VII: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline--a potential chloral-derived indol alkaloid in man". Archiv der Pharmazie. 323 (9): 567–569. doi:10.1002/ardp.19903230903. PMID 2288478.
  15. ^ a b Grote C, Clement HW, Wesemann W, Bringmann G, Feineis D, Riederer P, et al. (1995). "Biochemical lesions of the nigrostriatal system by TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) and derivatives". Journal of Neural Transmission. Supplementum. 46: 275–281. PMID 8821064.
  16. ^ Bringmann G, Münchbach M, Feineis D, Faulhaber K, Ihmels H (May 2001). "Studies on single-strand scissions to cell-free plasmid DNA by the dopaminergic neurotoxin 'TaClo' (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline)". Neuroscience Letters. 304 (1–2): 41–44. doi:10.1016/s0304-3940(01)01731-1. PMID 11335050.
  17. ^ Kochen W, Kohlmüller D, De Biasi P, Ramsay R (2003). "The Endogeneous Formation of Highly Chlorinated Tetrahydro-ß-Carbolines as a Possible Causative Mechanism in Idiopathic Parkinson's Disease". The endogeneous formation of highly chlorinated tetrahydro-beta-carbolines as a possible causative mechanism in idiopathic Parkinson's disease. Advances in Experimental Medicine and Biology. Vol. 527. pp. 253–263. doi:10.1007/978-1-4615-0135-0_29. ISBN 978-1-4613-4939-6. PMID 15206739.
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