title: Analytical characterization and pharmacological evaluation of the new psychoactive substance 4-fluoromethylphenidate (4F-MPH) and differentiation between the (±)-threo and (±)-erythro diastereomers.
abstract: Misuse of (±)-threo-methylphenidate (methyl-2-phenyl-2-(piperidin-2-yl)acetate; Ritalin®; MPH) has long been acknowledged, but the appearance of MPH analogs in the form of 'research chemicals' has only emerged in more recent years. 4-Fluoromethylphenidate (4F-MPH) is one of these recent examples. This study presents the identification and analytical characterization of two powdered 4F-MPH products that were obtained from an online vendor in 2015. Interestingly, the products appeared to have originated from two distinct batches given that one product consisted of (±)-threo-4F-MPH isomers whereas the second sample consisted of a mixture of (±)-threo and (±)-erythro 4F-MPH. Monoamine transporter studies using rat brain synaptosomes revealed that the biological activity of the 4F-MPH mixture resided with the (±)-threo and not the (±)-erythro isomers based on higher potencies determined for blockage of dopamine uptake (IC504F-MPHmixture= 66 nM vs. IC50(±)-threo = 61 nM vs. IC50(±)-erythro = 8,528 nM) and norepinephrine uptake (IC504F-MPHmixture= 45 nM vs. (±)-threo = 31 nM vs. IC50(±)-erythro = 3,779 nM). In comparison, MPH was three times less potent than (±)-threo-4F-MPH at the dopamine transporter (IC50= 131 nM) and around 2.5 times less potent at the norepinephrine transporter (IC50= 83 nM). Both substances were catecholamine selective with IC50values of 8,805 nM and >10,000 nM for (±)-threo-4F-MPH and MPH at the serotonin transporter. These findings suggest that the psychostimulant properties of (±)-threo-4F-MPH might be more potent in humans than MPH. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Department of Life and Physical Sciences, Faculty of Science and Health, Athlone Institute of Technology, Dublin Road, Athlone, Co. Westmeath, N37HD68, Ireland.|Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin 8, D08W9RT, Ireland.
authors.forename: Gavin
authors.identifier: http://orcid.org/0000-0002-2496-8396
authors.initials: G
authors.lastname: McLaughlin
authors.affiliation: Department of Life and Physical Sciences, Faculty of Science and Health, Athlone Institute of Technology, Dublin Road, Athlone, Co. Westmeath, N37HD68, Ireland.
authors.forename: Noreen
authors.initials: N
authors.lastname: Morris
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin 8, D08W9RT, Ireland.
authors.forename: Pierce V
authors.initials: PV
authors.lastname: Kavanagh
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin 8, D08W9RT, Ireland.|Forensic Science Ireland, Garda HQ, Phoenix Park, Dublin 8, D08HN3X, Ireland.
authors.forename: John D
authors.initials: JD
authors.lastname: Power
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin 8, D08W9RT, Ireland.|School of Chemical and Pharmaceutical Sciences, College of Sciences and Health, Dublin Institute of Technology, Kevin Street, Dublin 8, D08NF82, Ireland.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Dowling
authors.affiliation: School of Chemistry, Trinity College Dublin, College Green, Dublin 2, D02EV57, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Twamley
authors.affiliation: School of Chemistry, Trinity College Dublin, College Green, Dublin 2, D02EV57, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: School of Chemistry, Trinity College Dublin, College Green, Dublin 2, D02EV57, Ireland.
authors.forename: Gary
authors.initials: G
authors.lastname: Hessman
authors.affiliation: School of Chemical and Pharmaceutical Sciences, College of Sciences and Health, Dublin Institute of Technology, Kevin Street, Dublin 8, D08NF82, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Murphy
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Walther
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Simon D
authors.identifier: http://orcid.org/0000-0001-8632-5372
authors.initials: SD
authors.lastname: Brandt
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000737:chemistry*; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 4-fluoromethylphenidate; in vitro; monoamine transporters; new psychoactive substances; psychostimulants; methylphenidate