title: Monoamine transporter and receptor interaction profiles of a new series of designer cathinones.
abstract: Psychoactive β-keto amphetamines (cathinones) are sold as "bath salts" or "legal highs" and recreationally abused. We characterized the pharmacology of a new series of cathinones, including methedrone, 4-methylethcathinone (4-MEC), 3-fluoromethcathinone (3-FMC), pentylone, ethcathinone, buphedrone, pentedrone, and N,N-dimethylcathinone. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-HT) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporter, the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells, and binding affinity to monoamine transporters and receptors. All of the cathinones were potent NE uptake inhibitors but differed in their DA vs. 5-HT transporter inhibition profiles and monoamine release effects. Methedrone was a more potent 5-HT than DA transporter inhibitor and released NE and 5-HT similar to para-methoxymethamphetamine (PMMA), para-methoxyamphetamine (PMA), 4-methylthioamphetamine (4-MTA), and 3,4-methylenedioxymethamphetamine (MDMA). 4-MEC and pentylone equipotently inhibited all of the monoamine transporters and released 5-HT. Ethcathinone and 3-FMC inhibited NE and DA uptake and released NE, and 3-FMC also released DA similar to N-ethylamphetamine and methamphetamine. Pentedrone and N,N-dimethylcathinone were non-releasing NE and DA uptake inhibitors as previously shown for pyrovalerone cathinones. Buphedrone preferentially inhibited NE and DA uptake and also released NE. None of the cathinones bound to rodent trace amine-associated receptor 1, in contrast to the non-β-keto-amphetamines. None of the cathinones exhibited relevant binding to other monoamine receptors. In summary, we found considerable differences in the monoamine transporter interaction profiles among different cathinones and compared with related amphetamines.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Hebelstrasse 2, Basel CH-4031, Switzerland.
authors.forename: L D
authors.initials: LD
authors.lastname: Simmler
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Hebelstrasse 2, Basel CH-4031, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Rickli
authors.affiliation: Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: M C
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Hebelstrasse 2, Basel CH-4031, Switzerland. Electronic address: matthias.liechti@usb.ch.
authors.forename: M E
authors.initials: ME
authors.lastname: Liechti
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D002090:Butyrophenones / Q000494:pharmacology; D015198:Designer Drugs / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008744:Methylamines / Q000494:pharmacology; D010422:Pentanones / Q000494:pharmacology; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011427:Propiophenones / Q000494:pharmacology; D017982:Receptors, Biogenic Amine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000662:Amphetamines; D015306:Biogenic Monoamines; D002090:Butyrophenones; D015198:Designer Drugs; D018765:Dopamine Uptake Inhibitors; D008744:Methylamines; D010422:Pentanones; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D011427:Propiophenones; D017982:Receptors, Biogenic Amine; D017367:Selective Serotonin Reuptake Inhibitors; C572410:pentedrone; C571632:3-fluoromethcathinone; C585202:4-methylethcathinone; C572237:2-ethylamino-1-phenyl-propan-1-one; C000593098:pentylone; C558328:4-methoxymethcathinone; C572409:buphedrone; C000593099:N,N-dimethylcathinone
keywords: Bath salts; Dopamine; Norepinephrine; Serotonin; Transporter