substituted tetrahydroisoquinoline

{{Short description|Class of chemical compounds}}

File:Tetrahydroisoquinoline-structure.svg, the parent structure of this family of compounds.]]

A substituted tetrahydroisoquinoline is a tetrahydroisoquinoline with one or more chemical substituents.{{cite book | last1=Shulgin | first1=Alexander Theodore | last2=Perry | first2=Wendy E. | title=The Simple Plant Isoquinolines | publisher=Transform Press | date=2002 | isbn=978-0-9630096-2-3 | oclc=51006569 | ol=OL8521520M}}{{cite book | author = Keeper Trout & friends | title = Trout's Notes on The Cactus Alkaloids Nomenclature, Physical properties, Pharmacology & Occurrences (Sacred Cacti Fourth Edition, Part C: Cactus Chemistry: Section 1) | date = 2013 | publisher = Mydriatic Productions/Better Days Publishing | url = https://troutsnotes.com/pdf/C13_CactusAlkaloids.pdf}} Many simple tetrahydroisoquinoline alkaloids related to mescaline are known and occur naturally in cactus species such as peyote (Lophophora williamsii) and Pachycereus pringlei among many others.{{cite book | last=Lundström | first=Jan | title=The Alkaloids: Chemistry and Pharmacology | chapter=Chapter 6 Simple Isoquinoline Alkaloids | publisher=Elsevier | volume=21 | date=1983 | isbn=978-0-12-469521-4 | doi=10.1016/s0099-9598(08)60052-8 | pages=255–327 | quote=TABLE 1: SIMPLE ISOQUINOLINE ALKALOIDS [...] TABLE II SIMPLE ISOQUINOLINE ALKALOIDS IN THE FAMILY OF CACTACEAE [...]}} Simple tetrahydroisoquinolines may be thought of as cyclized phenethylamines. As an example, anhalinine may be thought of as a cyclized analogue of mescaline. The simple tetrahydroisoquinolines are analogous in concept to the β-carbolines and harmala alkaloids, which can be considered cyclized analogues of tryptamines.{{cite book | vauthors = Rommelspacher H, Susilo R | title = Progress in Drug Research | chapter = Tetrahydroisoquinolines and β-carbolines: Putative natural substances in plants and mammals | volume = 29 | issue = | pages = 415–459 | date = 1985 | pmid = 3911263 | doi = 10.1007/978-3-0348-9315-2_10 | isbn = 978-3-0348-9992-5 | chapter-url = }}

Some of the simple tetrahydroisoquinolines, for instance pellotine, are known to be pharmacologically active, although none are known to have hallucinogenic activity. Known activities of simple tetrahydroisoquinolines include sedative and hypnotic effects, monoamine oxidase inhibition, and convulsant effects, among various others.{{cite journal | last=Cassels | first=Bruce K. | title=Alkaloids of the Cactaceae — The Classics | journal=Natural Product Communications | volume=14 | issue=1 | date=2019 | issn=1934-578X | doi=10.1177/1934578X1901400123 | doi-access=free}} In the 2020s, various simple tetrahydroisoquinolines, like pellotine, were identified as serotonin 5-HT_1D receptor ligands, serotonin 5-HT₆ receptor partial agonists, and/or serotonin 5-HT₇ receptor inverse agonists.{{cite journal | vauthors = Poulie CB, Chan CB, Parka A, Lettorp M, Vos J, Raaschou A, Pottie E, Bundgaard MS, Sørensen LM, Cecchi CR, Märcher-Rørsted E, Bach A, Herth MM, Decker A, Jensen AA, Elfving B, Kretschmann AC, Stove CP, Kohlmeier KA, Cornett C, Janfelt C, Kornum BR, Kristensen JL | title = In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid | journal = ACS Pharmacol Transl Sci | volume = 6 | issue = 10 | pages = 1492–1507 | date = October 2023 | pmid = 37854625 | pmc = 10580395 | doi = 10.1021/acsptsci.3c00142 | url = }}{{cite journal | vauthors = Chan CB, Pottie E, Simon IA, Rossebø AG, Herth MM, Harpsøe K, Kristensen JL, Stove CP, Poulie CB | title = Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists | journal = ACS Chem Neurosci | volume = 16 | issue = 3 | pages = 439–451 | date = February 2025 | pmid = 39836645 | doi = 10.1021/acschemneuro.4c00667 | url = }} These actions, such as the serotonin 5-HT₆ and/or 5-HT₇ receptor interactions, may be involved in the sedative and hypnotic effects of some of these compounds.

Synthetic tetrahydroisoquinoline analogues of phenethylamines, including AMPH-CR, METH-CR, PMMA-CR, DOM-CR, N-methyl-DOM-CR, DOB-CR, TDIQ (MDA-CR), and MDMTHIQ (MDMA-CR), have been developed and characterized.Malmusi, L., Dukat, M., Young, R., Teitler, M., Darmani, N. A., Ahmad, B., ... & Glennon, R. A. (1996). 1, 2, 3, 4-Tetrahydroisoquinoline analogs of phenylalkylamine stimulants and hallucinogens. Medicinal Chemistry Research, 6(6), 400–411. https://scholar.google.com/scholar?cluster=16646102221398485716 "Conformationally constrained, 1,2,3,4-tetrahydroisoquinoline (TIQ) analogs of central stimulant (e.g. amphetamine) and hallucinogenic (e.g. DOM) phenylalkylamines were prepared and evaluated to determine the contribution to activity of this conformational restriction. The amphetamine-related TIQs failed to produce locomotor stimulation in mice and did not produce amphetamine-appropriate responding in tests of stimulus generalization in (+)amphetamine-trained rats. Hallucinogen-related TIQs lacked appreciable affinity for 5-HT2A serotonin receptors and did not produce DOM-like effects in tests of stimulus generalization in DOM-trained rats. It is concluded that the phenylalkylamine conformation represented by the TIQs is not a major contributor to these actions."Malmusi, L., Dukat, M., Young, R., Teitler, M., Darmani, N. A., Ahmad, B., ... & Glennon, R. A. (1996). 1,2,3,4-Tetrahydroisoquinoline and related analogs of the phenylalkylamine designer drug MDMA. Medicinal Chemistry Research, 6(6), 412–426. https://scholar.google.com/scholar?cluster=15073179555289853539 "1,2,3,4-Tetrahydroisoquinoline (TIQ) analogs of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) and its N-methyl derivative, MDMA, similar in structure to a TIQ metabolite of MDA, were prepared and examined (a) in tests of central stimulant activity in mice, (b) for their ability to bind at human 5-HT2A receptors, and (c) in tests of stimulus generalization in rats trained to discriminate MDMA from vehicle. In general, the TIQ analogs failed to display appreciable activity in any assay system. Conversely, certain 2-aminotetralin and 2-aminoindan analogs were active in the stimulus generalization studies. It is concluded that TIQ-like conformations do not account for the actions typically associated with MDA- and MDMA-related agents."{{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 = | quote = Nonetheless, it appears that conformational restriction of phenylalkylamine hallucinogens, stimulants, and designer drugs into a tetrahydroisoquinoline structure usually abolishes their respective actions (Malmusi et al., 1996b; Young et al., 1999a,b). [...] Table 6 Summary of stimulus generalization results of agents used in the present investigation [...]}}{{cite journal | vauthors = Young R, Glennon RA | title = The stimulus effect of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline is similar to that of cocaine but different from that of amphetamine | journal = Pharmacol Biochem Behav | volume = 71 | issue = 1–2 | pages = 205–213 | date = 2002 | pmid = 11812524 | doi = 10.1016/s0091-3057(01)00666-9 | url = }}{{cite journal | vauthors = Young R | title = TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): discovery, pharmacological effects, and therapeutic potential | journal = CNS Drug Rev | volume = 13 | issue = 4 | pages = 405–422 | date = 2007 | pmid = 18078426 | pmc = 6494129 | doi = 10.1111/j.1527-3458.2007.00022.x | url = }} In general, cyclization of stimulant, entactogen, and/or psychedelic phenethylamines into the corresponding tetrahydroisoquinolines results in abolition of the defining effects of these drugs as well as loss of their affinities for monoamine transporters and serotonin 5-HT₂ receptors. However, some of the tetrahydroisoquinoline forms, such as TDIQ, show selective affinity for α₂-adrenergic receptors and associated effects.