Characterization of 3,4-methylenedioxymethamphetamine (MDMA) enantiomers in vitro and in the MPTP-lesioned primate R-MDMA reduces severity of dyskinesia, whereas S-MDMA extends duration of ON-time.
l-3,4-dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinsons disease, but long-term l-DOPA administration is marred by the emergence of motor complications, namely, dyskinesia and a shortening of antiparkinsonian benefit (wearing-OFF). 3,4-methylenedioxymethamphetamine (MDMA) is unique in that it exerts antidyskinetic effects and may enhance antiparkinsonian actions of l-DOPA. MDMA is composed of two enantiomers with different pharmacological profiles here, we describe a novel enantiospecific synthesis of the two enantiomers and expand on the previous characterization of their pharmacology. R-MDMA (rectus-MDMA) is relatively selective for 5-HT(2A) receptors, whereas S-MDMA (sinister-MDMA) inhibits both serotonin (SERT) and dopamine transporters (DAT SERTDAT ratio of 10 to 1). R- or S-MDMA (1, 3, and 10 mgkg, s.c.) was administered in combination with l-DOPA (15 mgkg, s.c.) to six female common marmosets (Callithrix jacchus) rendered parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration of R-MDMA (3 and 10 mgkg), the severity of peak-dose dyskinesia was decreased (by 33 and 46%, respectively p < 0.05) although total ON-time was unchanged (approximately 220 min), the duration of ON-time with disabling dyskinesia was decreased by 90 min when compared to l-DOPA alone (69% reduction p < 0.05). S-MDMA (1 mgkg) increased the total ON-time by 88 min compared to l-DOPA alone (34% increase p < 0.05), though dyskinesia were exacerbated. These data suggest that racemic MDMA exerts simultaneous effects, reducing dyskinesia and extending ON-time, by 5-HT(2A) antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.