title: In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks.
abstract: Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography-high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC50values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC50values between 0.049 and 166μM, whereas four analogs inhibited also MAO-B with IC50values between 82 and 376μM. 7-Me-AMT provided the lowest IC50value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed.
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Wagmann
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Brandt
authors.affiliation: Department of Pharmacology and Therapeutics, Trinity Centre for Health and Sciences, St. James's Hospital, Dublin, Ireland.
authors.forename: Pierce V
authors.initials: PV
authors.lastname: Kavanagh
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Maurer
authors.affiliation: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany. Electronic address: markus.meyer@uks.eu.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Meyer
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D011619:Psychotropic Drugs / Q000737:chemistry / Q000633:toxicity*; D018570:Risk Assessment; D014363:Tryptamines / Q000737:chemistry / Q000633:toxicity*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011619:Psychotropic Drugs; D014363:Tryptamines; C015293:indopan; D008995:Monoamine Oxidase
keywords: Alpha-methyltryptamine analog new psychoactive substances; Drugs of abuse; IC(50) value; LC–HR-MS/MS; MAO inhibition