Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) EnantiomersIn Vitroand in the MPTP-Lesioned Primate:R-MDMA Reduces Severity of Dyskinesia, WhereasS-MDMA Extends Duration of ON-Time

The drug MDMA, composed of two mirror-image forms (enantiomers), shows promise for treating Parkinson's disease motor complications. R-MDMA reduced peak-dose dyskinesia severity by 33% at 3 mg/kg and 46% at 10 mg/kg, and cut the duration of disabling dyskinesia by 69% (90 minutes) without changing total ON-time. S-MDMA at 1 mg/kg extended total ON-time by 34% (88 minutes) but worsened dyskinesia. The findings suggest that racemic MDMA's simultaneous antidyskinetic and ON-time-extending effects arise from R-MDMA's action on 5-HT2A receptors and S-MDMA's inhibition of serotonin and dopamine transporters.

Study at a glance

Abstract

l -3,4-Dihydroxyphenylalanine ( l -DOPA) is the most effective treatment for Parkinson's 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; SERT/DAT ratio of 10 to 1). R - or S -MDMA (1, 3, and 10 mg/kg, s.c.) was administered in combination with l -DOPA (15 mg/kg, 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 mg/kg), the severity of peak-dose dyskinesia was decreased (by 33 and 46%, respectively; p < 0.05); although total ON-time was unchanged (∼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 mg/kg) 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.