A substituted tetrahydroisoquinoline is a

tetrahydroisoquinoline 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 mis ...

with one or more chemical substituents. Many simple tetrahydroisoquinoline

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

s related to

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

are known and occur naturally in

cactus A cactus (: cacti, cactuses, or less commonly, cactus) is a member of the plant family Cactaceae (), a family of the order Caryophyllales comprising about 127 genera with some 1,750 known species. The word ''cactus'' derives, through Latin, ...

species such as

peyote The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to glisten". p. ...

(''Lophophora williamsii'') and ''

Pachycereus pringlei ''Pachycereus pringlei'' (also known as Mexican giant cardon or elephant cactus) is a species of large cactus native to northwestern Mexico, in the states of Baja California, Baja California Sur, and Sonora. It is commonly known as ''cardón'', a ...

'' among many others. Simple tetrahydroisoquinolines may be thought of as

cyclized phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative compounds of phenethylamine which can be formed by ...

s. As an example,

anhalinine Anhalinine, also known as ''O''-methylanhalamine or mescaline-CR, is a tetrahydroisoquinoline alkaloid found in ''Lophophora williamsii'' (peyote) and other cacti. It is structurally related to mescaline and is a cyclized phenethylamine analogue ...

may be thought of as a cyclized analogue of mescaline. The simple tetrahydroisoquinolines are analogous in concept to the β-carbolines and

harmala alkaloid Harmala alkaloids are several alkaloids that act as monoamine oxidase inhibitors (MAOIs). These alkaloids are found in the seeds of ''Peganum harmala'' (also known as harmal or Syrian rue), as well as ''Banisteriopsis caapi'' (ayahuasca), leave ...

s, which can be considered cyclized analogues of

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

s. Some of the simple tetrahydroisoquinolines, for instance

pellotine Pellotine, also known as peyotline or ''N''-methylanhalonidine, is a tetrahydroisoquinoline alkaloid found in '' Lophophora'' species, in particular ''L. diffusa''. It is the second most common alkaloid found in ''Lophophora williamsii'' (peyo ...

, are known to be pharmacologically active, although none are known to have

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic activity. Known activities of simple tetrahydroisoquinolines include

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

and

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

effects,

monoamine oxidase inhibition Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especia ...

, and

convulsant A convulsant is a drug which induces convulsions or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to poor therapeutic indices. Most convulsant ...

effects, among various others. In the 2020s, various simple tetrahydroisoquinolines, like pellotine, were identified as

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_1D receptor

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

s, serotonin 5-HT₆ receptor

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

s, and/or serotonin 5-HT₇ receptor

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

s. 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 Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

tetrahydroisoquinoline analogues of phenethylamines, including AMPH-CR, METH-CR, PMMA-CR,

DOM-CR DOM-CR, or DOM/CR, an acronym of "DOM-conformationally restrained", is a tetrahydroisoquinoline (THIQ) and cyclized phenethylamine related to the psychedelics DOM and 2C-D. It is a cyclized THIQ analogue of DOM and 2C-D. DOM-CR shows more than ...

, ''N''-methyl-DOM-CR, DOB-CR,

TDIQ TDIQ, also known as MDTHIQ or MDA-CR, is a tetrahydroisoquinoline drug used in scientific research, which has anxiolytic and anorectic effects in animals. It has an unusual effects profile in animals, with the effects generalising to cocaine and ...

(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." In general, cyclization of

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

entactogen Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

, and/or

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

phenethylamines into the corresponding tetrahydroisoquinolines results in abolition of the defining effects of these drugs as well as loss of their affinities for

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s and

5-HT₂ receptors. However, some of the tetrahydroisoquinoline forms, such as TDIQ, show selective affinity for α₂-adrenergic receptors and associated effects.

List of simple tetrahydroisoquinolines

Simple tetrahydroisoquinoline alkaloids

Synthetic simple tetrahydroisoquinolines

Notes

References

External links