Pharmacological characterization of designer cathinones in vitro

Abstract

Background and purpose: Designer β-keto amphetamines (e.g. cathinones, 'bath salts' and 'research chemicals') have become popular recreational drugs, but their pharmacology is poorly characterized.

Experimental approach: We 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 results: Mephedrone, 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-β-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 implications: Cathinones 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.

Figure 1

Chemical structures of cathinones, related amphetamines and cocaine.

Figure 2

Monoamine uptake inhibition. Potencies of different drug concentrations to inhibit the accumulation of NA, DA and 5-HT into NA, DA and 5-HT transporter-transfected HEK 293 cells respectively. The data are expressed as the mean ± SEM of three to five independent experiments. The lines show the data fit by nonlinear regression. IC₅₀ values are presented in Table 2.

Figure 3

Dopamine and 5-HT release. HEK 293 cells that stably express the DA or 5-HT transporter were preloaded with [³H]-DA or [³H]-5-HT, respectively, washed and incubated with drugs. Transporter-mediated release is expressed as % reduction in monoamine cell content at the maximal drug concentration (100 μM) compared with controls. **P < 0.01, ***P < 0.001, significant effects compared with controls. The EC₅₀ values are shown in Table 3. The data are expressed as the mean ± SEM of three independent experiments.