title: In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1.
abstract: Trace amine-associated receptor 1 (TAAR1) has been implicated in the behavioral effects of amphetamine-type stimulant drugs in rodents. TAAR1 has also been suggested as a target for novel medications to treat psychostimulant addiction. We previously reported that binding affinities at TAAR1 can differ between structural analogs of psychostimulants, and species differences have been observed. In this study, we complement our previous findings with additional substances and the determination of functional activation potencies. In summary, we present here pharmacological in vitro profiles of 101 psychoactive substances at human, rat, and mouse TAAR1. p-Tyramine, β-phenylethylamine, and tryptamine were included as endogenous comparator compounds. Functional cAMP measurements and radioligand displacement assays were conducted with human embryonic kidney 293 cells that expressed human, rat, or mouse TAAR1. Most amphetamines, phenethylamine, and aminoindanes exhibited potentially physiologically relevant rat and mouse TAAR1 activation (EC50 < 5 µM) and showed full or partial (Emax < 80%) agonist properties. Cathinone derivatives, including mephedrone and methylenedioxypyrovalerone, exhibited weak (EC50 = 5-10 µM) to negligible (EC50 > 10 µM) binding properties at TAAR1. Pipradrols, including methylphenidate, exhibited no affinity for TAAR1. We found considerable species differences in activity at TAAR1 among the highly active ligands, with a rank order of rat > mouse > human. This characterization provides information about the pharmacological profile of psychoactive substances. The species differences emphasize the relevance of clinical studies to translationally complement rodent studies on the role of TAAR1 activity for psychoactive substances.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland (L.D.S., M.E.L.); and Neuroscience Research, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (D.B., S.C., M.C.H).
authors.forename: Linda D
authors.initials: LD
authors.lastname: Simmler
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland (L.D.S., M.E.L.); and Neuroscience Research, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (D.B., S.C., M.C.H).
authors.forename: Danièle
authors.initials: D
authors.lastname: Buchy
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland (L.D.S., M.E.L.); and Neuroscience Research, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (D.B., S.C., M.C.H).
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chaboz
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland (L.D.S., M.E.L.); and Neuroscience Research, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (D.B., S.C., M.C.H).
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland (L.D.S., M.E.L.); and Neuroscience Research, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (D.B., S.C., M.C.H) matthias.liechti@usb.ch.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Liechti
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010627:Phenethylamines / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000187:drug effects*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000494:pharmacology; D014439:Tyramine / Q000494:pharmacology; D000095383:Trace Amine-Associated Receptors
chemical_list: D000662:Amphetamines; D010627:Phenethylamines; D011619:Psychotropic Drugs; D043562:Receptors, G-Protein-Coupled; D014363:Tryptamines; D014439:Tyramine; D000095383:Trace Amine-Associated Receptors; C030820:tryptamine