Tetrahydroisoquinoline

THIQ is a conformationally restrained (CR) or cyclized analogue of β-phenethylamine and amphetamine and is also known as AMPH-CR.{{cite book | vauthors = Glennon RA, Young R | title=Drug Discrimination | chapter=Role of Stereochemistry in Drug Discrimination Studies | publisher=Wiley | date=5 August 2011 | isbn=978-0-470-43352-2 | doi=10.1002/9781118023150.ch4 | url=https://onlinelibrary.wiley.com/doi/10.1002/9781118023150.ch4 | access-date=22 May 2025 | page=129–161}}{{cite journal | vauthors = Glennon RA, Young R, Rangisetty JB | title = Further characterization of the stimulus properties of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline | journal = Pharmacol Biochem Behav | volume = 72 | issue = 1-2 | pages = 379–387 | date = May 2002 | pmid = 11900809 | doi = 10.1016/s0091-3057(01)00768-7 | url = }} In contrast to amphetamine however, THIQ fails to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that it lacks stimulant effects. Similar findings have been made for other tetrahydroisoquinoline analogues of psychoactive phenethylamines, for instance DOM-CR. In any case, THIQ does substitute for TDIQ (MDTIQ), a selective α₂-adrenergic receptor ligand, indicating that it is not pharmacologically inactive.

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.{{Cite journal| title = Selenium dioxide catalyzed oxidation of secondary amines with hydrogen peroxide. Simple synthesis of nitrones from secondary amines| journal = Tetrahedron Letters| issue = 21 | first1 = S.| volume = 28| year = 1987| doi = 10.1016/S0040-4039(00)96130-6| last1 = Murahashi| pages = 2383–2386}}

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.{{Cite journal

| pmid = 350073

| year = 1978

| last1 = Blum | first1 = K.

| last2 = Hamilton

| last3 = Hirst

| last4 = Wallace

| title = Putative role of isoquinoline alkaloids in alcoholism: a link to opiates

| volume = 2

| issue = 2

| pages = 113–120

| journal = Alcoholism: Clinical and Experimental Research

| doi = 10.1111/j.1530-0277.1978.tb04710.x | first2 = M. G. | first3 = M. | first4 = J. E.

}},{{Cite journal

| pmid = 7202207

| year = 1982

| last1 = Altshuler | first1 = H. L.

| last2 = Shippenberg

| title = Tetrahydroisoquinoline and opioid substrates of alcohol actions

| volume = 90

| pages = 329–344

| journal = Progress in Clinical and Biological Research

}}, {{Cite journal

| pmid = 2656285

| year = 1989

| last1 = Myers | first1 = R. D.

| title = Isoquinolines, beta-carbolines and alcohol drinking: involvement of opioid and dopaminergic mechanisms

| volume = 45

| issue = 5

| pages = 436–443

| journal = Experientia

| doi = 10.1007/BF01952025

| s2cid = 1513683

}} This theory has now been discredited and is no longer generally accepted by the scientific community,{{Cite journal

| pmid = 8727243

| year = 1996

| last1 = Myers | first1 = R. D.

| title = Tetrahydroisoquinolines and alcoholism: where are we today?

| volume = 20

| issue = 3

| pages = 498–500

| journal = Alcoholism: Clinical and Experimental Research

| doi = 10.1111/j.1530-0277.1996.tb01081.x

}}, {{Cite journal

| pmid = 8891913

| year = 1996

| last1 = Musshoff | first1 = F.

| last2 = Daldrup

| last3 = Bonte

| last4 = Leitner

| last5 = Lesch

| title = Formaldehyde-derived tetrahydroisoquinolines and tetrahydro-beta-carbolines in human urine

| volume = 683

| issue = 2

| pages = 163–176

| journal = Journal of Chromatography B

| doi = 10.1016/0378-4347(96)00106-5 | first2 = T. | first3 = W. | first4 = A. | first5 = O. M.

}}, {{Cite journal

| doi = 10.1016/S0741-8329(98)00080-9

| pmid = 10456568

| year = 1999

| last1 = Sällström Baum | first1 = S.

| last2 = Hill

| last3 = Kiianmaa

| last4 = Rommelspacher

| title = Effect of ethanol on (R)- and (S)-salsolinol, salsoline, and THP in the nucleus accumbens of AA and ANA rats

| volume = 18

| issue = 2–3

| pages = 165–169

| journal = Alcohol (Fayetteville, N.Y.) | first2 = R. | first3 = K. | first4 = H.

}}, {{Cite journal

| pmid = 15654290

| year = 2005

| last1 = Musshoff | first1 = F.

| last2 = Lachenmeier

| last3 = Schmidt

| last4 = Dettmeyer

| last5 = Madea

| title = Systematic regional study of dopamine, norsalsolinol, and (R/S)-salsolinol levels in human brain areas of alcoholics

| volume = 29

| issue = 1

| pages = 46–52

| journal = Alcoholism: Clinical and Experimental Research

| doi = 10.1097/01.ALC.0000150011.81102.C2 | first2 = D. W. | first3 = P. | first4 = R. | first5 = B.

}} 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.{{cite journal |vauthors=Kotake Y, Tasaki Y, Makino Y, Ohta S, Hirobe M |title=1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF |journal=Journal of Neurochemistry |volume=65 |issue=6 |pages=2633–8 |date=December 1995 |pmid=7595560 |doi= 10.1046/j.1471-4159.1995.65062633.x|s2cid=39449026 }}{{cite journal |vauthors=McNaught KS, Carrupt PA, Altomare C, Cellamare S, Carotti A, Testa B, Jenner P, Marsden CD |title=Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease |journal=Biochemical Pharmacology |volume=56 |issue=8 |pages=921–33 |date=October 1998 |pmid=9776302 |doi= 10.1016/S0006-2952(98)00142-7}}{{cite journal |vauthors=Lorenc-Koci E, Smiałowska M, Antkiewicz-Michaluk L, Gołembiowska K, Bajkowska M, Wolfarth S |title=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 |journal=Neuroscience |volume=95 |issue=4 |pages=1049–59 |year=2000 |pmid=10682712 |doi= 10.1016/S0306-4522(99)00511-4|s2cid=13549697 }}{{cite journal |vauthors=Storch A, Ott S, Hwang YI, Ortmann R, Hein A, Frenzel S, Matsubara K, Ohta S, Wolf HU, Schwarz J |title=Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter |journal=Biochemical Pharmacology |volume=63 |issue=5 |pages=909–20 |date=March 2002 |pmid=11911843 |doi= 10.1016/S0006-2952(01)00922-4}}{{cite journal |vauthors=Lorenc-Koci E, Antkiewicz-Michaluk L, Kamińska A, Lenda T, Zieba B, Wierońska J, Smiałowska M, Schulze G, Rommelspacher H |title=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 |journal=Neuroscience |volume=156 |issue=4 |pages=973–86 |date=October 2008 |pmid=18809471 |doi=10.1016/j.neuroscience.2008.08.050 |s2cid=44658852 }}{{cite journal |vauthors=Kobayashi H, Fukuhara K, Tada-Oikawa S, Yada Y, Hiraku Y, Murata M, Oikawa S |title=The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease |journal=Journal of Neurochemistry |volume=108 |issue=2 |pages=397–407 |date=January 2009 |pmid=19012744 |doi=10.1111/j.1471-4159.2008.05774.x |doi-access=free }}

{{Main|Substituted tetrahydroisoquinoline}}

The tetrahydroisoquinoline skeleton is present in a number of drugs,{{cite journal | last1 = Scott | first1 = Jack D. | last2 = Williams | first2 = Robert M. | year = 2002 | title = Chemistry and Biology of the Tetrahydroisoquinoline Antitumor Antibiotics | journal = Chemical Reviews | volume = 102 | issue = 5| pages = 1669–1730 | doi = 10.1021/cr010212u | pmid = 11996547 }} such as tubocurarine, one of the quaternary ammonium muscle relaxants. Drugs based on 4-substituted tetrahydroisoquinolines include nomifensine{{Cite journal| last1 = Schneider | first1 = C. S.| last2 = Weber| last3 = Daniel| last4 = Bechtel| last5 = Boeke-Kuhn| title = Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives| journal = Journal of Medicinal Chemistry| volume = 27| issue = 9| pages = 1150–1155| year = 1984 | doi = 10.1021/jm00375a011 | first2 = K. H. | first3 = H. | first4 = W. D. | first5 = K.| pmid = 6471069}} and diclofensine. They can be prepared by N-alkylation of benzyl amines with haloacetophenones.{{Patent|BG|49761}} Naturally occurring tetrahydroisoquinolines include cherylline[http://www.chemspider.com/Chemical-Structure.81315.html cherylline] and latifine.

Esproquin,{{cite journal|last1=Gray|first1=Allan P.|last2=Shiley|first2=Richard H.|title=Preparation and cardiovascular actions of a group of tetrahydroisoquinoline derivatives|journal=Journal of Medicinal Chemistry|volume=16|issue=7|year=1973|pages=859–861|issn=0022-2623|doi=10.1021/jm00265a028|pmid=4146907}} which shows hypotensive activity by virtue of its α-adrenergic blocking properties, is made from THIQ.

• Substituted tetrahydroisoquinoline

{{Reflist}}

{{Phenethylamines}}