UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset

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

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Abstract

L-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of l-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with l-DOPA, UWA-121 extended duration of ON-time when compared to l-DOPA/vehicle treatment (by 40%, P <0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P <0.05) and ON-time without psychosis-like behaviours when compared to l-DOPA/vehicle treatment (by 345%, P <0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with l-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance l-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD. © 2014 Published by Elsevier Ltd.
Original languageEnglish
Pages (from-to)76-87
JournalNeuropharmacology
Volume82
DOIs
Publication statusPublished - 2014

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Callithrix
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dyskinesias
Serotonin Uptake Inhibitors
Levodopa
Psychotic Disorders
Dopamine
Serotonin
Parkinson Disease
Pharmacology
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
N-methyl-1-cyclopropyl-1-piperonylmethylamine
Parkinsonian Disorders
Therapeutic Uses

Cite this

@article{16232d9a41bb4720be129f86ec77b910,
title = "UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset",
abstract = "L-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of l-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with l-DOPA, UWA-121 extended duration of ON-time when compared to l-DOPA/vehicle treatment (by 40{\%}, P <0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215{\%}, P <0.05) and ON-time without psychosis-like behaviours when compared to l-DOPA/vehicle treatment (by 345{\%}, P <0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with l-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance l-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD. {\circledC} 2014 Published by Elsevier Ltd.",
author = "P. Huot and T.H. Johnston and K.D. Lewis and J.B. Koprich and M.G. Reyes and S.H. Fox and Matthew Piggott and J.M. Brotchie",
year = "2014",
doi = "10.1016/j.neuropharm.2014.01.012",
language = "English",
volume = "82",
pages = "76--87",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier",

}

UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset. / Huot, P.; Johnston, T.H.; Lewis, K.D.; Koprich, J.B.; Reyes, M.G.; Fox, S.H.; Piggott, Matthew; Brotchie, J.M.

In: Neuropharmacology, Vol. 82, 2014, p. 76-87.

Research output: Contribution to journalArticle

TY - JOUR

T1 - UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset

AU - Huot, P.

AU - Johnston, T.H.

AU - Lewis, K.D.

AU - Koprich, J.B.

AU - Reyes, M.G.

AU - Fox, S.H.

AU - Piggott, Matthew

AU - Brotchie, J.M.

PY - 2014

Y1 - 2014

N2 - L-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of l-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with l-DOPA, UWA-121 extended duration of ON-time when compared to l-DOPA/vehicle treatment (by 40%, P <0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P <0.05) and ON-time without psychosis-like behaviours when compared to l-DOPA/vehicle treatment (by 345%, P <0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with l-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance l-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD. © 2014 Published by Elsevier Ltd.

AB - L-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of l-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with l-DOPA, UWA-121 extended duration of ON-time when compared to l-DOPA/vehicle treatment (by 40%, P <0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P <0.05) and ON-time without psychosis-like behaviours when compared to l-DOPA/vehicle treatment (by 345%, P <0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with l-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance l-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD. © 2014 Published by Elsevier Ltd.

U2 - 10.1016/j.neuropharm.2014.01.012

DO - 10.1016/j.neuropharm.2014.01.012

M3 - Article

VL - 82

SP - 76

EP - 87

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -