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.
Identifieur interne : 000616 ( PubMed/Checkpoint ); précédent : 000615; suivant : 000617UWA-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.
Auteurs : Philippe Huot [Canada] ; Tom H. Johnston [Canada] ; Katie D. Lewis [Australie] ; James B. Koprich [Canada] ; M Gabriela Reyes [Canada] ; Susan H. Fox [Canada] ; Matthew J. Piggott [Australie] ; Jonathan M. Brotchie [Canada]Source :
- Neuropharmacology [ 1873-7064 ] ; 2014.
English descriptors
- KwdEn :
- 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, Serotonin Uptake Inhibitors (pharmacology), Severity of Illness Index, Time Factors.
- MESH :
- chemical , adverse effects : Antiparkinson Agents, Levodopa.
- chemical , chemical synthesis : Benzodioxoles, Methylamines.
- chemical , chemistry : Benzodioxoles, Methylamines.
- chemical , pharmacology : Antiparkinson Agents, Benzodioxoles, Dopamine Uptake Inhibitors, Levodopa, Methylamines, Serotonin Uptake Inhibitors.
- chemically induced : Mental Disorders.
- drug effects : Behavior, Animal, Motor Activity.
- drug therapy : Parkinsonian Disorders.
- Animals, Callithrix, Drug Therapy, Combination, Dyskinesia, Drug-Induced, Female, Molecular Structure, Rats, Sprague-Dawley, Severity of Illness Index, Time Factors.
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.
DOI: 10.1016/j.neuropharm.2014.01.012
PubMed: 24447715
Affiliations:
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Fox</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J" last="Piggott">Matthew J. Piggott</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009</wicri:regionArea><wicri:noRegion>Perth 6009</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada. 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Electronic address: p.huot@umontreal.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H" last="Johnston">Tom H. Johnston</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Lewis, Katie D" sort="Lewis, Katie D" uniqKey="Lewis K" first="Katie D" last="Lewis">Katie D. Lewis</name><affiliation wicri:level="1"><nlm:affiliation>School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009</wicri:regionArea><wicri:noRegion>Perth 6009</wicri:noRegion></affiliation></author><author><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B" last="Koprich">James B. Koprich</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Reyes, M Gabriela" sort="Reyes, M Gabriela" uniqKey="Reyes M" first="M Gabriela" last="Reyes">M Gabriela Reyes</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J" last="Piggott">Matthew J. Piggott</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009</wicri:regionArea><wicri:noRegion>Perth 6009</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada. Electronic address: brotchie@uhnres.utoronto.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8</wicri:regionArea><wicri:noRegion>ON M5T 2S8</wicri:noRegion></affiliation></author></analytic><series><title level="j">Neuropharmacology</title><idno type="eISSN">1873-7064</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiparkinson Agents (adverse effects)</term><term>Antiparkinson Agents (pharmacology)</term><term>Behavior, Animal (drug effects)</term><term>Benzodioxoles (chemical synthesis)</term><term>Benzodioxoles (chemistry)</term><term>Benzodioxoles (pharmacology)</term><term>Callithrix</term><term>Dopamine Uptake Inhibitors (pharmacology)</term><term>Drug Therapy, Combination</term><term>Dyskinesia, Drug-Induced</term><term>Female</term><term>Levodopa (adverse effects)</term><term>Levodopa (pharmacology)</term><term>Mental Disorders (chemically induced)</term><term>Methylamines (chemical synthesis)</term><term>Methylamines (chemistry)</term><term>Methylamines (pharmacology)</term><term>Molecular Structure</term><term>Motor Activity (drug effects)</term><term>Parkinsonian Disorders (drug therapy)</term><term>Rats, Sprague-Dawley</term><term>Serotonin Uptake Inhibitors (pharmacology)</term><term>Severity of Illness Index</term><term>Time Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Antiparkinson Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Benzodioxoles</term><term>Methylamines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Benzodioxoles</term><term>Methylamines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiparkinson Agents</term><term>Benzodioxoles</term><term>Dopamine Uptake Inhibitors</term><term>Levodopa</term><term>Methylamines</term><term>Serotonin Uptake Inhibitors</term></keywords><keywords scheme="MESH" qualifier="chemically induced" xml:lang="en"><term>Mental Disorders</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Behavior, Animal</term><term>Motor Activity</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinsonian Disorders</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Callithrix</term><term>Drug Therapy, Combination</term><term>Dyskinesia, Drug-Induced</term><term>Female</term><term>Molecular Structure</term><term>Rats, Sprague-Dawley</term><term>Severity of Illness Index</term><term>Time Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24447715</PMID><DateCreated><Year>2014</Year><Month>05</Month><Day>19</Day></DateCreated><DateCompleted><Year>2015</Year><Month>01</Month><Day>09</Day></DateCompleted><DateRevised><Year>2014</Year><Month>05</Month><Day>19</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1873-7064</ISSN><JournalIssue CitedMedium="Internet"><Volume>82</Volume><PubDate><Year>2014</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Neuropharmacology</Title><ISOAbbreviation>Neuropharmacology</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>76-87</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.neuropharm.2014.01.012</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0028-3908(14)00019-7</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2014. Published by Elsevier Ltd.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Huot</LastName><ForeName>Philippe</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Johnston</LastName><ForeName>Tom H</ForeName><Initials>TH</Initials><AffiliationInfo><Affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lewis</LastName><ForeName>Katie D</ForeName><Initials>KD</Initials><AffiliationInfo><Affiliation>School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Perth 6009, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Koprich</LastName><ForeName>James B</ForeName><Initials>JB</Initials><AffiliationInfo><Affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reyes</LastName><ForeName>M Gabriela</ForeName><Initials>MG</Initials><AffiliationInfo><Affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fox</LastName><ForeName>Susan H</ForeName><Initials>SH</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Piggott</LastName><ForeName>Matthew J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brotchie</LastName><ForeName>Jonathan M</ForeName><Initials>JM</Initials><AffiliationInfo><Affiliation>Toronto Western Research Institute, Krembil Discovery Tower, 8KD-402, 60 Leonard Street, Toronto, ON M5T 2S8, Canada. Electronic address: brotchie@uhnres.utoronto.ca.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>01</Month><Day>18</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Neuropharmacology</MedlineTA><NlmUniqueID>0236217</NlmUniqueID><ISSNLinking>0028-3908</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000978">Antiparkinson Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D052117">Benzodioxoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018765">Dopamine Uptake Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008744">Methylamines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C579241">N-methyl-1-cyclopropyl-1-piperonylmethylamine</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D017367">Serotonin Uptake Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>46627O600J</RegistryNumber><NameOfSubstance UI="D007980">Levodopa</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000978" MajorTopicYN="N">Antiparkinson Agents</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001522" MajorTopicYN="N">Behavior, Animal</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D052117" MajorTopicYN="N">Benzodioxoles</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002144" MajorTopicYN="N">Callithrix</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018765" MajorTopicYN="N">Dopamine Uptake Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004359" MajorTopicYN="N">Drug Therapy, Combination</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004409" MajorTopicYN="N">Dyskinesia, Drug-Induced</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007980" MajorTopicYN="N">Levodopa</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001523" MajorTopicYN="N">Mental Disorders</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="N">chemically induced</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008744" MajorTopicYN="N">Methylamines</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009043" MajorTopicYN="N">Motor Activity</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020734" MajorTopicYN="N">Parkinsonian Disorders</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017367" MajorTopicYN="N">Serotonin Uptake Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012720" MajorTopicYN="N">Severity of Illness Index</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013997" MajorTopicYN="N">Time Factors</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Dyskinesia</Keyword><Keyword MajorTopicYN="N">MPTP</Keyword><Keyword MajorTopicYN="N">ON-time</Keyword><Keyword MajorTopicYN="N">Parkinson's disease</Keyword><Keyword MajorTopicYN="N">UWA-121</Keyword><Keyword MajorTopicYN="N">l-DOPA</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2013</Year><Month>05</Month><Day>31</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2013</Year><Month>11</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2014</Year><Month>01</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>1</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>1</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>1</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">24447715</ArticleId><ArticleId IdType="pii">S0028-3908(14)00019-7</ArticleId><ArticleId IdType="doi">10.1016/j.neuropharm.2014.01.012</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Australie</li><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Huot, Philippe" sort="Huot, Philippe" uniqKey="Huot P" first="Philippe" last="Huot">Philippe Huot</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H" last="Johnston">Tom H. Johnston</name><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B" last="Koprich">James B. Koprich</name><name sortKey="Reyes, M Gabriela" sort="Reyes, M Gabriela" uniqKey="Reyes M" first="M Gabriela" last="Reyes">M Gabriela Reyes</name></country><country name="Australie"><noRegion><name sortKey="Lewis, Katie D" sort="Lewis, Katie D" uniqKey="Lewis K" first="Katie D" last="Lewis">Katie D. Lewis</name></noRegion><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J" last="Piggott">Matthew J. Piggott</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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