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

P. Huot, T.H. Johnston, Katie Lewis, J.B. Koprich, M.G. Reyes, S.H. Fox, Matthew Piggott, J.M. Brotchie

Research output: Contribution to journalArticle

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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-HT2A 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-1,2,3,6tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration ofR-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 (similar to 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-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.
Original languageEnglish
Pages (from-to)7190-7198
JournalJournal of Neuroscience
Volume31
DOIs
Publication statusPublished - 2011

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N-Methyl-3,4-methylenedioxyamphetamine
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dyskinesias
Primates
Levodopa
Antiparkinson Agents
Callithrix
Serotonin
Pharmacology
Receptor, Serotonin, 5-HT2A
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
In Vitro Techniques
Parkinsonian Disorders
Parkinson Disease

Cite this

@article{4903d92d39f848b5b9cca002efdf3fe4,
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-HT2A 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-1,2,3,6tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration ofR-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 (similar to 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-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.",
author = "P. Huot and T.H. Johnston and Katie Lewis and J.B. Koprich and M.G. Reyes and S.H. Fox and Matthew Piggott and J.M. Brotchie",
year = "2011",
doi = "10.1523/JNEUROSCI.1171-11.2011",
language = "English",
volume = "31",
pages = "7190--7198",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience (USA)",

}

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. / Huot, P.; Johnston, T.H.; Lewis, Katie; Koprich, J.B.; Reyes, M.G.; Fox, S.H.; Piggott, Matthew; Brotchie, J.M.

In: Journal of Neuroscience, Vol. 31, 2011, p. 7190-7198.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Huot, P.

AU - Johnston, T.H.

AU - Lewis, Katie

AU - Koprich, J.B.

AU - Reyes, M.G.

AU - Fox, S.H.

AU - Piggott, Matthew

AU - Brotchie, J.M.

PY - 2011

Y1 - 2011

N2 - 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-HT2A 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-1,2,3,6tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration ofR-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 (similar to 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-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.

AB - 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-HT2A 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-1,2,3,6tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration ofR-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 (similar to 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-HT2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.

U2 - 10.1523/JNEUROSCI.1171-11.2011

DO - 10.1523/JNEUROSCI.1171-11.2011

M3 - Article

VL - 31

SP - 7190

EP - 7198

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

ER -