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 CF3 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.

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

“…These results are consistent with previous microdialysis studies in both rats (Baumann et al, 2000;Kehr et al, 2011) and nonhuman primates (Laruelle et al, 1997;Murnane et al, 2010;Sawyer et al, 2012), and confirm the sensitivity of this microdialysis procedure to changes in NAc DA and 5-HT levels produced by agents that have been extensively evaluated. Also consistent with a previous MCAT microdialysis study (Cozzi et al, 2013), MCAT displayed a greater potency to increase NAc DA versus 5-HT levels. The present study extends these previous findings by examining a longer time course of MCAT-induced DA and 5-HT effects and using an i.p.…”

“…Like methamphetamine, MCAT functions as a monoamine transporter substrate that selectively promotes release of dopamine (DA) and norepinephrine over serotonin (5-HT) (Cozzi et al, 1999(Cozzi et al, , 2013Baumann et al, 2012). Consistent with MCAT's Schedule I controlled substance classification in the United States, MCAT increases striatal and nucleus accumbens (NAc) DA levels as measured by in vivo microdialysis in rats (Gygi et al, 1997;Cozzi et al, 2013). Furthermore, MCAT functions as a reinforcer in nonhuman primate drug self-administration procedures (Kaminski and Griffiths, 1994) and produces an abuse-related facilitation of intracranial self-stimulation (ICSS) in rats .…”

Electrophysiological Actions of Synthetic Cathinones on Monoamine Transporters

“…Further uptake inhibition assays in rat brain synaptosomes employing MDPV analogs confirmed that the α-alkyl chain is essential for hDAT affinity, whereas the methylenedioxy group does not affect affinity (101). Substituting a trifluoromethyl on the 3 or 4 position of MCAT’s ring increases the compound’s selectivity towards SERT over NET and DAT (102). Second generation MEPH analogs also elicit release through SERT and DAT (5).…”

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

“…Thus, the carbon atoms 3 and 5 exchange their numbering on going from tautomer a to b. There is ample information in the literature that a trifluoromethyl group is an interesting pharmacophore [26,27,28] even in pyrazole derivatives [29,30,31] including the well-known anti-inflammatory Celecoxib [32]. 19 F, nitromethane and CFCl 3 respectively.…”