Substituted tetrahydroisoquinoline

A substituted tetrahydroisoquinoline is a tetrahydroisoquinoline with one or more chemical substituents.^[1][2] 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.^[1][2][3][4] Simple tetrahydroisoquinolines may be thought of as cyclized phenethylamines.^[1][2] As an example, anhalinine may be thought of as a cyclized analogue of mescaline.^[1][2] The simple tetrahydroisoquinolines are analogous in concept to the β-carbolines and harmala alkaloids, which can be considered cyclized analogues of tryptamines.^[5]

Some of the simple tetrahydroisoquinolines, for instance pellotine, are known to be pharmacologically active, although none are known to have hallucinogenic activity.^[1][2][4] Known activities of simple tetrahydroisoquinolines include sedative and hypnotic effects, monoamine oxidase inhibition, and convulsant effects, among various others.^[4][2] 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.^[6][7] 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.^[6][7]

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.^{[8][9][10][11][12]} 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.^{[8][9][10][11][12]} However, some of the tetrahydroisoquinoline forms, such as TDIQ, show selective affinity for α₂-adrenergic receptors and associated effects.^[12][10]