title: Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs.
abstract: Cathinones are a class of drugs used to treat various medical conditions including depression, obesity, substance abuse, and muscle spasms. Some "designer" cathinones, such as methcathinone, mephedrone, and methylone, are used nonclinically for their stimulant or entactogenic properties. Given the recent rise in nonmedical use of designer cathinones, we aimed to improve understanding of cathinone pharmacology by investigating analogs of methcathinone with a CF(3) substituent at the 2-, 3-, or 4-position of the phenyl ring (TFMAPs). We compared the TFMAPs with methcathinone for effects on monoamine uptake transporter function in vitro and in vivo, and for effects on locomotor activity in rats. At the serotonin transporter (SERT), 3-TFMAP and 4-TFMAP were 10-fold more potent than methcathinone as uptake inhibitors and as releasing agents, but 2-TFMAP was both a weak uptake inhibitor and releaser. At the norepinephrine and dopamine transporters (NET and DAT), all TFMAP isomers were less potent than methcathinone as uptake inhibitors and releasers. In vivo, 4-TFMAP released 5-HT, but not dopamine, in rat nucleus accumbens and did not affect locomotor activity, whereas methcathinone increased both 5-HT and dopamine and produced locomotor stimulation. These experiments reveal that TFMAPs are substrates for the monoamine transporters and that phenyl ring substitution at the 3- or 4-position increases potency at SERT but decreases potency at NET and DAT, resulting in selectivity for SERT. The TFMAPs might have a therapeutic value for a variety of medical and psychiatric conditions and may have lower abuse liability compared to methcathinone due to their decreased DAT activity.
authors.affiliation: Neuropharmacology Laboratory, 2695 Medical Sciences Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA. cozzi@wisc.edu
authors.forename: Nicholas V
authors.initials: NV
authors.lastname: Cozzi
authors.forename: Simon D
authors.initials: SD
authors.lastname: Brandt
authors.forename: Paul F
authors.initials: PF
authors.lastname: Daley
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Andreas
authors.initials: A
authors.lastname: Tulzer
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011427:Propiophenones; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C047806:monomethylpropion; D004298:Dopamine