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.

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1 This study examined the e ects of chronic exposure of rats to 3,4-methylenedioxymethamphetamine (MDMA) on [ 3 H]5-hydroxytryptamine ([ 3 H]5-HT) re-uptake into puri®ed rat brain synaptosomes, 5-HT-induced isometric contraction of aortic rings and [ 3 H]5-HT re-uptake into rat aorta. 2 Rats were administered MDMA (20 mg kg 71 i.p.) twice daily over 4 days. One, 7, 14 or 21 days post treatment, whole brain synaptosomes and descending thoracic aortic rings were prepared for investigation. 3 Chronic MDMA treatment signi®cantly reduced the maximum rate (V max ) of speci®c higha nity [ 3 H]5-HT re-uptake 1 day after treatment and for up to 21 days post-®nal administration of MDMA. Direct application of MDMA (100 mM) abolished synaptosomal re-uptake of [ 3 H]5-HT in vitro. 4 Chronic MDMA administration signi®cantly reduced the maximum contraction (E max ) to 5-HT at 1 and 7 days after treatment, but not at 14 or 21 days. 5 Chronic MDMA administration had no e ect on sodium-dependent [ 3 H]5-HT re-uptake into aorta 1 day after treatment, nor did 100 mM MDMA have any direct e ect on [ 3 H]5-HT uptake into aortic rings in vitro. 6 These results show, for the ®rst time, an altered responsiveness of vascular tissue to MDMA after chronic administration. In addition, they demonstrate a di erence in the sensitivity of central and peripheral 5-HT uptake systems to chronic MDMA exposure, and suggest that the action of MDMA in the cardiovascular system does not arise from a direct e ect of MDMA on peripheral 5-HT transport.