Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs.
Nicholas V. Cozzi, Simon D. Brandt, Paul F. Daley, John S. Partilla, Richard B Rothman, Andreas Tulzer, Harald H. Sitte, Michael H Baumann
European Journal of Pharmacology November 21, 2012 DOI: 10.1016/j.ejphar.2012.11.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats (in vivo microdialysis and locomotor activity experiments); in vitro transporter assays |
| Interventions | 3- methcathinone |
| Topics | Serotonin |
| Keywords | Nucleus accumbens Animals Rats, sprague-dawley Dopamine Propiophenones Motor activity Male |
| Key findings | TFMAPs are substrates for monoamine transporters; 3- or 4-phenyl ring substitution increases potency at SERT but decreases potency at NET and DAT, yielding SERT selectivity. In vivo, 4-TFMAP released 5-HT but not dopamine in rat nucleus accumbens and did not affect locomotor activity, unlike methcathinone, which increased both 5-HT and dopamine and stimulated locomotion. The authors propose that TFMAPs might have therapeutic value and lower abuse liability than methcathinone due to decreased DAT activity. |
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.
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| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
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- Discriminative-Stimulus Effects of Synthetic Cathinones in Squirrel Monkeys The International Journal of Neuropsychopharmacology April 26, 2021
- 2-Aminoindan and its Ring-Substituted Derivatives Interact with Plasma Membrane Monoamine Transporters and α2-Adrenergic Receptors Psychopharmacology March 1, 2019
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Cites 7
- The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology July 19, 2010
- Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class Journal of Medicinal Chemistry October 1, 1986
- The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. Journal of Biological Chemistry May 25, 2012
- Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats British Journal of Pharmacology May 26, 2011
- The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology December 14, 2011
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