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

Philippe Huot; Tom H Johnston; Katie D Lewis; James B Koprich; M Gabriela Reyes; Susan H Fox; Matthew J Piggott; Jonathan M Brotchie

doi:10.1016/j.neuropharm.2014.01.012

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

Neuropharmacology. 2014 Jul:82:76-87. doi: 10.1016/j.neuropharm.2014.01.012. Epub 2014 Jan 18.

Authors

Philippe Huot¹, Tom H Johnston², Katie D Lewis³, James B Koprich², M Gabriela Reyes², Susan H Fox⁴, Matthew J Piggott⁵, Jonathan M Brotchie⁶

Affiliations

¹ Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. Electronic address: p.huot@umontreal.ca.
² Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
³ School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.
⁴ Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada.
⁵ School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009, Australia. Electronic address: matthew.piggott@uwa.edu.au.
⁶ Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada. Electronic address: brotchie@uhnres.utoronto.ca.

PMID: 24447715
DOI: 10.1016/j.neuropharm.2014.01.012

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.

Keywords: Dyskinesia; MPTP; ON-time; Parkinson's disease; UWA-121; l-DOPA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiparkinson Agents / adverse effects
Antiparkinson Agents / pharmacology*
Behavior, Animal / drug effects
Benzodioxoles / chemical synthesis
Benzodioxoles / chemistry
Benzodioxoles / pharmacology*
Callithrix
Dopamine Uptake Inhibitors / pharmacology
Drug Therapy, Combination
Dyskinesia, Drug-Induced
Female
Levodopa / adverse effects
Levodopa / pharmacology*
Mental Disorders / chemically induced
Methylamines / chemical synthesis
Methylamines / chemistry
Methylamines / pharmacology*
Molecular Structure
Motor Activity / drug effects
Parkinsonian Disorders / drug therapy*
Rats, Sprague-Dawley
Selective Serotonin Reuptake Inhibitors / pharmacology
Severity of Illness Index
Time Factors

Substances

Antiparkinson Agents
Benzodioxoles
Dopamine Uptake Inhibitors
Methylamines
N-methyl-1-cyclopropyl-1-piperonylmethylamine
Serotonin Uptake Inhibitors
Levodopa