title: 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.
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 (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 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.
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: Katie D
authors.initials: KD
authors.lastname: Lewis
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Reyes
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Piggott
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002144:Callithrix; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D007980:Levodopa / Q000627:therapeutic use / Q000633:toxicity*; D020267:MPTP Poisoning / Q000188:drug therapy; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013237:Stereoisomerism
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D018817:N-Methyl-3,4-methylenedioxyamphetamine