Comparative potencies of 3,4‐methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5‐HT transport in mammalian cell lines

Illegal ecstasy tablets often contain compounds similar to MDMA whose effects are unknown. This study measured how well eight such compounds block the noradrenaline and serotonin transporters, key targets of MDMA in the brain. 2,3-MDMA was less potent than MDMA at the serotonin transporter but equally potent at the noradrenaline transporter. 2CB and BDB were less potent at the noradrenaline transporter but equally potent at the serotonin transporter. MBDB, DMMA, MDOH, and MDMA metabolites HMA and HMMA were all less potent than MDMA at both transporters. These results clarify how chemical structure affects the activity of MDMA-like compounds.

Study at a glance

Abstract

Background and purpose: Illegal ‘ecstasy’ tablets frequently contain 3,4‐methylenedioxymethamphetamine (MDMA)‐like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [ 3 H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [ 3 H]5‐HT uptake into HEK293 cells stably transfected with the 5‐HT transporter (SERT). Experimental approach: Concentration–response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4‐hydroxy‐3‐methoxyamphetamine (HMA), 4‐hydroxy‐3‐methoxymethamphetamine (HMMA), 3,4‐methylenedioxy‐ N ‐hydroxyamphetamine (MDOH), 2,5‐dimethoxy‐4‐bromophenylethylamine (2CB), 3,4‐dimethoxymethamphetamine (DMMA), 3,4‐methylenedioxyphenyl‐2‐butanamine (BDB), 3,4‐methylenedioxyphenyl‐ N ‐methyl‐2‐butanamine (MBDB) and 2,3‐methylenedioxymethamphetamine (2,3‐MDMA). Key results: 2,3‐MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT. Conclusions and implications: This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA. British Journal of Pharmacology (2007) 152 , 1121–1130; doi: 10.1038/sj.bjp.0707473 ; published online 24 September 2007