Pharmacological characterization of designer cathinones in vitro

Abstract

BACKGROUND AND PURPOSEDesigner b-keto amphetamines (e.g. cathinones, 'bath salts' and 'research chemicals') have become popular recreational drugs, but their pharmacology is poorly characterized. EXPERIMENTAL APPROACHWe determined the potencies of cathinones to inhibit DA, NA and 5-HT transport into transporter-transfected HEK 293 cells, DA and 5-HT efflux from monoamine-preloaded cells, and monoamine receptor binding affinity. KEY RESULTSMephedrone, methylone, ethylone, butylone and naphyrone acted as non-selective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced the release of 5-HT, similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone and flephedrone, similar to amphetamine and methamphetamine, acted as preferential DA and NA uptake inhibitors and induced the release of DA. Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) were highly potent and selective DA and NA transporter inhibitors but unlike amphetamines did not evoke the release of monoamines. The non-b-keto amphetamines are trace amine-associated receptor 1 ligands, whereas the cathinones are not. All the cathinones showed high blood-brain barrier permeability in an in vitro model; mephedrone and MDPV exhibited particularly high permeability. CONCLUSIONS AND IMPLICATIONSCathinones have considerable pharmacological differences that form the basis of their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is probably associated with a considerable risk of addiction. AbbreviationsBBB, blood-brain barrier; DA, dopamine; DAT, dopamine transporter; MBDB, 3,4-methlyenedioxyphenyl-N-methyl-2-

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

“…Hence, the obtained value of mephedrone brain/plasma ratio of 1.85 demonstrates a high and good central nervous system penetration. Moreover this result is in agreement with those obtained by Simmler et al (2012) in an in vitro model of the human blood brain barrier.…”

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

“…WE Fantegrossi et al Simmler et al, 2012). However, METH has previously been shown to substitute for cocaine in mice trained to discriminate cocaine from saline (eg, Rodvelt et al, 2011), and we have previously reported that cocaine produces full generalization in mice trained to discriminate S( þ )-MDMA or R( À )-MDMA from saline (Murnane et al, 2009).…”

“…In this regard, the structurally similar pyrovalerone has been shown to stimulate spontaneous locomotor activity in rodents (Fauquet et al, 1976;Vaugeois et al, 1993) and to induce stimulant-like actions in humans (Holliday et al, 1964;Goldberg et al, 1973). More recently, it was demonstrated that pyrovalerone has cocaine-like effects at dopamine reuptake transporters (Heron et al, 1994;Tidjane Corera et al, 2001;Meltzer et al, 2006) and that these effects are also apparent in MDPV itself (Baumann et al, 2012b;Simmler et al, 2012). In an early study, orally administered MDPV was demonstrated to induce locomotor-stimulant effects in mice (Fuwa et al, 2007), and this year, studies have reported that MDPV elicits locomotor stimulation (Huang et al, 2012) and possesses reinforcing effects in rats (Watterson et al, 2012).…”

Human Pharmacology of Mephedrone in Comparison with MDMA

“…Studies in animal models indicate that mephedrone acts as a monoamine releaser and a reuptake inhibitor (Simmler et al, 2013;Baumann et al, 2012;López-Arnau et al, 2012). It has, therefore, been shown to increase dopamine in a similar manner to amphetamine and produce more serotonin increase (5-HT) than MDMA (Baumann et al, 2012;Kehr et al, 2011).…”