Pharmacological profile of mephedrone analogs and related new psychoactive substances

Abstract

The predominant actions on serotonin vs. dopamine transporters suggest that dimethylmethcathinones, 4-MA, and MMAI cause entactogenic effects similar to 3,4-methylenedioxymethamphetamine, whereas 3-MMC, 5-IT, and N-methyl-2-AI have more stimulant-type properties like amphetamine. Because of pharmacological and structural similarity to mephedrone, similar health risks can be expected for these analogs. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors

“…All of the aminoindans tested in this study have moderate to high affinity for α 2adrenoceptor subtypes. Consistent with our data, previous studies reported that 2-AI, MDAI, MMAI, and 5-iodo-2-aminoindan (5-IAI) bind to α 2 receptors with affinity in the submicromolar or low micromolar range (Marona-Lewicka and Nichols 1994;Iversen et al 2013;Simmler et al 2014b;Luethi et al 2017). Activity in the series peaked with the unsubstituted compound 2-AI, which bound to the three subtypes with nanomolar affinity (α 2A K i = 134 nM, α 2B K i = 211 nM, and α 2C K i = 41 nM).…”

“…5-MeO-AI exhibited some selectivity for SERT-mediated release, having 6-fold lower potency at NET and 20-fold lower potency at DAT. Consistent with previous reports (Johnson et al 1991a;Marona-Lewicka and Nichols 1994;Luethi et al 2017), MMAI is highly selective SERT releaser, with 100-fold lower potency at NET and DAT. In addition to their effects on monoamine release, the aminoindans had relatively high affinity for α 2 -adrenoceptor subtypes.…”

Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

“…Inhibition of the human NET, DAT and SERT was assessed in HEK 293 cells (Invitrogen, Zug, Switzerland) stably transfected with the respective human transporter as previously described (Tatsumi et al, ; Hysek et al, ; Luethi et al, ). The cells were cultured in DMEM (Gibco, Life Technologies, Zug, Switzerland) with 10% fetal bovine serum (Gibco) and 250 μg·mL −1 Geneticin (Gibco) to 70–90% confluence, detached and then resuspended (3 × 10 6 cells·mL −1 ) in Krebs ‐ Ringer bicarbonate buffer (Sigma‐Aldrich, Buchs, Switzerland).…”

“…Substances that inhibit the monoamine uptake may also be monoamine transporter substrates and release monoamines via the transporter. The potential of the drugs which inhibited the uptake to also initiate transporter‐mediated noradrenaline or 5‐HT efflux was assessed in HEK 293 cells that overexpressed the respective human transporter as previously described (Simmler et al, , ; Luethi et al, ). Briefly, 100 000 cells per well were cultured overnight in a poly‐D‐lysine coated XF24 cell culture microplate (Seahorse Biosciences, North Billerica, MA, USA).…”

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT2A receptors: In vitro and in vivo evidence

“…Reports show that certain SCs have appreciable affinity at 7-transmembrane, G proteincoupled receptors, [21][22][23][24] and one publication reports that 2,3dimethylmethcathinone is a 5-HT 2A receptor (5-HT 2A R) agonist. 25 Few studies, however, have closely considered such off-targets as liabilities, and we are aware of no studies that have linked off-target activity to specific behavioral outcomes.…”