Abstract

Synthetic cathinones are components of "bath salts" and have physical and psychological side effects including hypertension, paranoia, and hallucinations. Herein we report interactions of 20 "bath salt" components with human dopamine, serotonin, and norepinephrine transporters (hDAT, hSERT, and hNET, respectively) heterologously expressed in HEK 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (Ki values) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-PPP, α-PBP, α-PHP, PV-8, 3,4-MDPPP, 3,4-MDPBP, 4-MePPP, α-PVP, 4-MeO- α-PVP, α-PVT and pentedrone, and hDAT>hSERT>hNET for pentylone. Increasing the α-carbon chain length increased the affinity and potency of the α-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT>hNET>hSERT except α-PPP and α-PVT, which had highest potencies at hNET. They did not induce [³H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine (METH) and 3,4-methylenedioxymethylamphetamine (MDMA) are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloro-methcathinone and 4-fluoroamphetamine were substrates at all three transporters; MDAI and 4-MEC were substrates primarily at hSERT and hNET, while ethylone and 5-methoxy-methylone were substrates only at hSERT and induced [³H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus Ki/IC₅₀ ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone and MDAI, which have higher potency at hSERT than hDAT, may have empathogen psychoactivity.