Tetrahydroisoquinoline Explained

Tetrahydroisoquinoline (TIQ or THIQ) is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is miscible with most organic solvents. The tetrahydroisoquinoline skeleton is encountered in a number of bioactive compounds and drugs.[1]

Reactions

As a secondary amine, tetrahydroisoquinoline has weakly basic properties and forms salts with strong acids. It can be dehydrogenated to give isoquinoline and hydrogenated to decahydroisoquinoline. Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide.[2]

Toxicology

Tetrahydroisoquinoline derivatives may be formed in the body as metabolites of some drugs, and this was once thought to be involved in the development of alcoholism.[3] This theory has now been discredited and is no longer generally accepted by the scientific community,[4] but endogenous production of neurotoxic tetrahydroisoquinoline derivatives such as norsalsolinol continue to be investigated as possible causes for some conditions such as Parkinson's disease.[5] [6] [7] [8] [9] [10]

Tetrahydroisoquinolines

The tetrahydroisoquinoline skeleton is present in a number of drugs,[11] such as tubocurarine, one of the quaternary ammonium muscle relaxants. Drugs based on 4-substituted tetrahydroisoquinolines include nomifensine[12] and diclofensine. They can be prepared by N-alkylation of benzyl amines with haloacetophenones. Naturally occurring tetrahydroisoquinolines include cherylline[13] and latifine.

Esproquin,[14] which shows hypotensive activity by virtue of its α-adrenergic blocking properties, is made from THIQ.

Notes and References

  1. 10.1039/A908537H . 17 . Saturated nitrogen heterocycles . 2000 . Journal of the Chemical Society, Perkin Transactions 1 . 2862–2892 . Mitchenson . Andrew.
  2. Selenium dioxide catalyzed oxidation of secondary amines with hydrogen peroxide. Simple synthesis of nitrones from secondary amines. Tetrahedron Letters. 21 . S.. 28. 1987. 10.1016/S0040-4039(00)96130-6. Murahashi. 2383–2386.
  3. 350073. 1978. Blum . K.. Hamilton. Hirst. Wallace. Putative role of isoquinoline alkaloids in alcoholism: a link to opiates. 2. 2. 113–120. Alcoholism: Clinical and Experimental Research. 10.1111/j.1530-0277.1978.tb04710.x . M. G. . M. . J. E..,7202207. 1982. Altshuler . H. L.. Shippenberg. Tetrahydroisoquinoline and opioid substrates of alcohol actions. 90. 329–344. Progress in Clinical and Biological Research., 2656285. 1989. Myers . R. D.. Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms. 45. 5. 436–443. Experientia. 10.1007/BF01952025. 1513683.
  4. 8727243. 1996. Myers . R. D.. Tetrahydroisoquinolines and alcoholism: where are we today?. 20. 3. 498–500. Alcoholism: Clinical and Experimental Research. 10.1111/j.1530-0277.1996.tb01081.x., 8891913. 1996. Musshoff . F.. Daldrup. Bonte. Leitner. Lesch. Formaldehyde-derived tetrahydroisoquinolines and tetrahydro-beta-carbolines in human urine. 683. 2. 163–176. Journal of Chromatography B. 10.1016/0378-4347(96)00106-5 . T. . W. . A. . O. M.., 10.1016/S0741-8329(98)00080-9. 10456568. 1999. Sällström Baum . S.. Hill. Kiianmaa. Rommelspacher. Effect of ethanol on (R)- and (S)-salsolinol, salsoline, and THP in the nucleus accumbens of AA and ANA rats. 18. 2–3. 165–169. Alcohol (Fayetteville, N.Y.) . R. . K. . H.., 15654290. 2005. Musshoff . F.. Lachenmeier. Schmidt. Dettmeyer. Madea. Systematic regional study of dopamine, norsalsolinol, and (R/S)-salsolinol levels in human brain areas of alcoholics. 29. 1. 46–52. Alcoholism: Clinical and Experimental Research. 10.1097/01.ALC.0000150011.81102.C2 . D. W. . P. . R. . B..
  5. Kotake Y, Tasaki Y, Makino Y, Ohta S, Hirobe M . 1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF . Journal of Neurochemistry . 65 . 6 . 2633–8 . December 1995 . 7595560 . 10.1046/j.1471-4159.1995.65062633.x. 39449026 .
  6. McNaught KS, Carrupt PA, Altomare C, Cellamare S, Carotti A, Testa B, Jenner P, Marsden CD . Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease . . 56 . 8 . 921–33 . October 1998 . 9776302 . 10.1016/S0006-2952(98)00142-7.
  7. Lorenc-Koci E, Smiałowska M, Antkiewicz-Michaluk L, Gołembiowska K, Bajkowska M, Wolfarth S . Effect of acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline on muscle tone, metabolism of dopamine in the striatum and tyrosine hydroxylase immunocytochemistry in the substantia nigra, in rats . Neuroscience . 95 . 4 . 1049–59 . 2000 . 10682712 . 10.1016/S0306-4522(99)00511-4. 13549697 .
  8. Storch A, Ott S, Hwang YI, Ortmann R, Hein A, Frenzel S, Matsubara K, Ohta S, Wolf HU, Schwarz J . Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter . Biochemical Pharmacology . 63 . 5 . 909–20 . March 2002 . 11911843 . 10.1016/S0006-2952(01)00922-4.
  9. Lorenc-Koci E, Antkiewicz-Michaluk L, Kamińska A, Lenda T, Zieba B, Wierońska J, Smiałowska M, Schulze G, Rommelspacher H . The influence of acute and chronic administration of 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline on the function of the nigrostriatal dopaminergic system in rats . Neuroscience . 156 . 4 . 973–86 . October 2008 . 18809471 . 10.1016/j.neuroscience.2008.08.050 . 44658852 .
  10. Kobayashi H, Fukuhara K, Tada-Oikawa S, Yada Y, Hiraku Y, Murata M, Oikawa S . The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease . Journal of Neurochemistry . 108 . 2 . 397–407 . January 2009 . 19012744 . 10.1111/j.1471-4159.2008.05774.x . free .
  11. Scott . Jack D. . Williams . Robert M. . 2002 . Chemistry and Biology of the Tetrahydroisoquinoline Antitumor Antibiotics . Chemical Reviews . 102 . 5. 1669–1730 . 10.1021/cr010212u . 11996547 .
  12. Schneider . C. S.. Weber. Daniel. Bechtel. Boeke-Kuhn. Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives. Journal of Medicinal Chemistry. 27. 9. 1150–1155. 1984 . 10.1021/jm00375a011 . K. H. . H. . W. D. . K.. 6471069.
  13. http://www.chemspider.com/Chemical-Structure.81315.html cherylline
  14. Gray. Allan P.. Shiley. Richard H.. Preparation and cardiovascular actions of a group of tetrahydroisoquinoline derivatives. Journal of Medicinal Chemistry. 16. 7. 1973. 859–861. 0022-2623. 10.1021/jm00265a028. 4146907.

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