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.
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.
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.
Philippe
P
Huot
Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
Tom H
TH
Johnston
School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.
Katie D
KD
Lewis
Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
James B
JB
Koprich
Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
M Gabriela
MG
Reyes
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.
Susan H
SH
Fox
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.
Matthew J
MJ
Piggott
Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada. Electronic address: brotchie@uhnres.utoronto.ca.
Jonathan M
JM
Brotchie
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002144:Callithrix; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology*; D001523:Mental Disorders / Q000139:chemically induced; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012720:Severity of Illness Index; D013997:Time Factors
D000978:Antiparkinson Agents; D052117:Benzodioxoles; D018765:Dopamine Uptake Inhibitors; D007980:Levodopa; D008744:Methylamines; D017367:Selective Serotonin Reuptake Inhibitors; C579241:N-methyl-1-cyclopropyl-1-piperonylmethylamine
Dyskinesia; MPTP; ON-time; Parkinson's disease; UWA-121; l-DOPA