Tetrahydroisoquinoline

Last updated
Tetrahydroisoquinoline
Tetrahydroisoquinoline-structure.svg
Names
Preferred IUPAC name
1,2,3,4-Tetrahydroisoquinoline
Other names
AMPH-CR; "Amphetamine-Conformationally Restrained"; AMPH-THIQ; AMPH/THIQ
Identifiers
3D model (JSmol)
AbbreviationsTIQ, THIQ
ChEMBL
ChemSpider
ECHA InfoCard 100.001.864 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 202-050-0
PubChem CID
RTECS number
  • NX4900000
UNII
  • InChI=1S/C9H11N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-4,10H,5-7H2 Yes check.svgY
    Key: UWYZHKAOTLEWKK-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C9H11N/c1-2-4-9-7-10-6-5-8(9)3-1/h1-4,10H,5-7H2
    Key: UWYZHKAOTLEWKK-UHFFFAOYAB
  • c1ccc2c(c1)CCNC2
Properties
C9H11N
Molar mass 133.19 g/mol
AppearanceDeep yellow liquid
Density 1.05 g/mL
Melting point −30 °C (−22 °F; 243 K)
Boiling point 235 to 239 °C (455 to 462 °F; 508 to 512 K)
Hazards
GHS labelling: [1]
GHS-pictogram-acid.svg GHS-pictogram-skull.svg GHS-pictogram-silhouette.svg
Danger
H301, H310, H314, H332, H371, H412
P260, P261, P262, P264, P270, P271, P273, P280, P301+P310, P301+P330+P331, P302+P350, P302+P352, P303+P361+P353, P304+P312, P304+P340, P305+P351+P338, P309+P311, P310, P312, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, P501
Flash point 99 °C (210 °F; 372 K) (closed cup)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Tetrahydroisoquinoline (TIQ or THIQ), also known as AMPH-CR, 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. [2] [3]

Contents

Pharmacology

THIQ is a conformationally restrained (CR) or cyclized analogue of β-phenethylamine and amphetamine and is also known as AMPH-CR. [4] [5] In contrast to amphetamine however, THIQ fails to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that it lacks stimulant effects. [4] [5] Similar findings have been made for other tetrahydroisoquinoline analogues of psychoactive phenethylamines, for instance DOM-CR. [4] [5] In any case, THIQ does substitute for TDIQ (MDTIQ), a selective α2-adrenergic receptor ligand, indicating that it is not pharmacologically inactive. [4] [5]

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. [6]

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. [7] This theory has now been discredited and is no longer generally accepted by the scientific community, [8] 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. [9] [10] [11] [12] [13] [14]

Tetrahydroisoquinolines

The tetrahydroisoquinoline skeleton is present in a number of drugs, [3] such as tubocurarine, one of the quaternary ammonium muscle relaxants. Drugs based on 4-substituted tetrahydroisoquinolines include nomifensine [15] and diclofensine. They can be prepared by N-alkylation of benzyl amines with haloacetophenones. [16] Naturally occurring tetrahydroisoquinolines include cherylline [17] and latifine.

Esproquin, [18] which shows hypotensive activity by virtue of its α-adrenergic blocking properties, is made from THIQ.

See also

References

  1. ↑ "1,2,3,4-Tetrahydroisoquinoline". pubchem.ncbi.nlm.nih.gov. Retrieved 12 December 2021.
  2. ↑ Mitchenson, Andrew (2000). "Saturated nitrogen heterocycles". Journal of the Chemical Society, Perkin Transactions 1 (17): 2862–2892. doi:10.1039/A908537H.
  3. 1 2 Scott, Jack D.; Williams, Robert M. (2002). "Chemistry and Biology of the Tetrahydroisoquinoline Antitumor Antibiotics". Chemical Reviews. 102 (5): 1669–1730. doi:10.1021/cr010212u. PMID   11996547.
  4. 1 2 3 4 Glennon RA, Young R (5 August 2011). "Role of Stereochemistry in Drug Discrimination Studies". Drug Discrimination. Wiley. p. 129–161. doi:10.1002/9781118023150.ch4. ISBN   978-0-470-43352-2 . Retrieved 22 May 2025.
  5. 1 2 3 4 Glennon RA, Young R, Rangisetty JB (May 2002). "Further characterization of the stimulus properties of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline". Pharmacol Biochem Behav. 72 (1–2): 379–387. doi:10.1016/s0091-3057(01)00768-7. PMID   11900809.
  6. ↑ Murahashi, S. (1987). "Selenium dioxide catalyzed oxidation of secondary amines with hydrogen peroxide. Simple synthesis of nitrones from secondary amines". Tetrahedron Letters. 28 (21): 2383–2386. doi:10.1016/S0040-4039(00)96130-6.
  7. ↑ Blum, K.; Hamilton, M. G.; Hirst, M.; Wallace, J. E. (1978). "Putative role of isoquinoline alkaloids in alcoholism: a link to opiates". Alcoholism: Clinical and Experimental Research. 2 (2): 113–120. doi:10.1111/j.1530-0277.1978.tb04710.x. PMID   350073.,Altshuler, H. L.; Shippenberg (1982). "Tetrahydroisoquinoline and opioid substrates of alcohol actions". Progress in Clinical and Biological Research. 90: 329–344. PMID   7202207., Myers, R. D. (1989). "Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms". Experientia. 45 (5): 436–443. doi:10.1007/BF01952025. PMID   2656285. S2CID   1513683.
  8. ↑ Myers, R. D. (1996). "Tetrahydroisoquinolines and alcoholism: where are we today?". Alcoholism: Clinical and Experimental Research. 20 (3): 498–500. doi:10.1111/j.1530-0277.1996.tb01081.x. PMID   8727243., Musshoff, F.; Daldrup, T.; Bonte, W.; Leitner, A.; Lesch, O. M. (1996). "Formaldehyde-derived tetrahydroisoquinolines and tetrahydro-beta-carbolines in human urine". Journal of Chromatography B. 683 (2): 163–176. doi:10.1016/0378-4347(96)00106-5. PMID   8891913., Sällström Baum, S.; Hill, R.; Kiianmaa, K.; Rommelspacher, H. (1999). "Effect of ethanol on (R)- and (S)-salsolinol, salsoline, and THP in the nucleus accumbens of AA and ANA rats". Alcohol (Fayetteville, N.Y.). 18 (2–3): 165–169. doi:10.1016/S0741-8329(98)00080-9. PMID   10456568., Musshoff, F.; Lachenmeier, D. W.; Schmidt, P.; Dettmeyer, R.; Madea, B. (2005). "Systematic regional study of dopamine, norsalsolinol, and (R/S)-salsolinol levels in human brain areas of alcoholics". Alcoholism: Clinical and Experimental Research. 29 (1): 46–52. doi:10.1097/01.ALC.0000150011.81102.C2. PMID   15654290.
  9. ↑ Kotake Y, Tasaki Y, Makino Y, Ohta S, Hirobe M (December 1995). "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. doi:10.1046/j.1471-4159.1995.65062633.x. PMID   7595560. S2CID   39449026.
  10. ↑ McNaught KS, Carrupt PA, Altomare C, Cellamare S, Carotti A, Testa B, Jenner P, Marsden CD (October 1998). "Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease". Biochemical Pharmacology . 56 (8): 921–33. doi:10.1016/S0006-2952(98)00142-7. PMID   9776302.
  11. ↑ Lorenc-Koci E, Smiałowska M, Antkiewicz-Michaluk L, Gołembiowska K, Bajkowska M, Wolfarth S (2000). "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. doi:10.1016/S0306-4522(99)00511-4. PMID   10682712. S2CID   13549697.
  12. ↑ Storch A, Ott S, Hwang YI, Ortmann R, Hein A, Frenzel S, Matsubara K, Ohta S, Wolf HU, Schwarz J (March 2002). "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. doi:10.1016/S0006-2952(01)00922-4. PMID   11911843.
  13. ↑ Lorenc-Koci E, Antkiewicz-Michaluk L, Kamińska A, Lenda T, Zieba B, Wierońska J, Smiałowska M, Schulze G, Rommelspacher H (October 2008). "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. doi:10.1016/j.neuroscience.2008.08.050. PMID   18809471. S2CID   44658852.
  14. ↑ Kobayashi H, Fukuhara K, Tada-Oikawa S, Yada Y, Hiraku Y, Murata M, Oikawa S (January 2009). "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. doi: 10.1111/j.1471-4159.2008.05774.x . PMID   19012744.
  15. ↑ Schneider, C. S.; Weber, K. H.; Daniel, H.; Bechtel, W. D.; Boeke-Kuhn, K. (1984). "Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives". Journal of Medicinal Chemistry . 27 (9): 1150–1155. doi:10.1021/jm00375a011. PMID   6471069.
  16. ↑ BG 49761
  17. ↑ cherylline
  18. ↑ Gray, Allan P.; Shiley, Richard H. (1973). "Preparation and cardiovascular actions of a group of tetrahydroisoquinoline derivatives". Journal of Medicinal Chemistry. 16 (7): 859–861. doi:10.1021/jm00265a028. ISSN   0022-2623. PMID   4146907.


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