L-745,870 reduces L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.
Identifieur interne : 000A39 ( PubMed/Corpus ); précédent : 000A38; suivant : 000A40L-745,870 reduces L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.
Auteurs : Philippe Huot ; Tom H. Johnston ; James B. Koprich ; Ahmed Aman ; Susan H. Fox ; Jonathan M. BrotchieSource :
- The Journal of pharmacology and experimental therapeutics [ 1521-0103 ] ; 2012.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology), Animals, Antiparkinson Agents (blood), Antiparkinson Agents (cerebrospinal fluid), Antiparkinson Agents (pharmacokinetics), Antiparkinson Agents (pharmacology), Brain (drug effects), Brain (metabolism), Drug Interactions, Dyskinesias (blood), Dyskinesias (cerebrospinal fluid), Dyskinesias (drug therapy), Dyskinesias (metabolism), Female, Levodopa (pharmacology), Macaca, Male, Motor Activity (drug effects), Parkinson Disease (blood), Parkinson Disease (cerebrospinal fluid), Parkinson Disease (drug therapy), Parkinson Disease (metabolism), Pyridines (blood), Pyridines (cerebrospinal fluid), Pyridines (pharmacokinetics), Pyridines (pharmacology), Pyrroles (blood), Pyrroles (cerebrospinal fluid), Pyrroles (pharmacokinetics), Pyrroles (pharmacology), Receptors, Dopamine D4 (antagonists & inhibitors), Receptors, Dopamine D4 (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Receptors, Dopamine D4.
- chemical , blood : Antiparkinson Agents, Pyridines, Pyrroles.
- chemical , cerebrospinal fluid : Antiparkinson Agents, Pyridines, Pyrroles.
- chemical , metabolism : Receptors, Dopamine D4.
- chemical , pharmacokinetics : Antiparkinson Agents, Pyridines, Pyrroles.
- chemical , pharmacology : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Antiparkinson Agents, Levodopa, Pyridines, Pyrroles.
- blood : Dyskinesias, Parkinson Disease.
- cerebrospinal fluid : Dyskinesias, Parkinson Disease.
- drug effects : Brain, Motor Activity.
- drug therapy : Dyskinesias, Parkinson Disease.
- metabolism : Brain, Dyskinesias, Parkinson Disease.
- Animals, Drug Interactions, Female, Macaca, Male.
Abstract
L-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (L-745,870), a potent and selective dopamine D(4) receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of L-745,870 in combination with L-DOPA. To guarantee D(4) selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of L-745,870. Coadministration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with L-DOPA alone (P < 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (-56%; P < 0.01). Brain levels of L-745,870 (∼600 ng/g) were within the range at which L-745,870 provides selective D(4) receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D(4) receptor antagonists represent a potential therapeutic approach for L-DOPA-induced dyskinesia. It is noteworthy that L-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.
DOI: 10.1124/jpet.112.195693
PubMed: 22619253
Links to Exploration step
pubmed:22619253Le document en format XML
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Koprich</name></author><author><name sortKey="Aman, Ahmed" sort="Aman, Ahmed" uniqKey="Aman A" first="Ahmed" last="Aman">Ahmed Aman</name></author><author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. 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Brotchie</name></author></analytic><series><title level="j">The Journal of pharmacology and experimental therapeutics</title><idno type="eISSN">1521-0103</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)</term><term>Animals</term><term>Antiparkinson Agents (blood)</term><term>Antiparkinson Agents (cerebrospinal fluid)</term><term>Antiparkinson Agents (pharmacokinetics)</term><term>Antiparkinson Agents (pharmacology)</term><term>Brain (drug effects)</term><term>Brain (metabolism)</term><term>Drug Interactions</term><term>Dyskinesias (blood)</term><term>Dyskinesias (cerebrospinal fluid)</term><term>Dyskinesias (drug therapy)</term><term>Dyskinesias (metabolism)</term><term>Female</term><term>Levodopa (pharmacology)</term><term>Macaca</term><term>Male</term><term>Motor Activity (drug effects)</term><term>Parkinson Disease (blood)</term><term>Parkinson Disease (cerebrospinal fluid)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (metabolism)</term><term>Pyridines (blood)</term><term>Pyridines (cerebrospinal fluid)</term><term>Pyridines (pharmacokinetics)</term><term>Pyridines (pharmacology)</term><term>Pyrroles (blood)</term><term>Pyrroles (cerebrospinal fluid)</term><term>Pyrroles (pharmacokinetics)</term><term>Pyrroles (pharmacology)</term><term>Receptors, Dopamine D4 (antagonists & inhibitors)</term><term>Receptors, Dopamine D4 (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Receptors, Dopamine D4</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Antiparkinson Agents</term><term>Pyridines</term><term>Pyrroles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="cerebrospinal fluid" xml:lang="en"><term>Antiparkinson Agents</term><term>Pyridines</term><term>Pyrroles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptors, Dopamine D4</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Antiparkinson Agents</term><term>Pyridines</term><term>Pyrroles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term><term>Antiparkinson Agents</term><term>Levodopa</term><term>Pyridines</term><term>Pyrroles</term></keywords><keywords scheme="MESH" qualifier="blood" xml:lang="en"><term>Dyskinesias</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="cerebrospinal fluid" xml:lang="en"><term>Dyskinesias</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brain</term><term>Motor Activity</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesias</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term><term>Dyskinesias</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Drug Interactions</term><term>Female</term><term>Macaca</term><term>Male</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">L-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (L-745,870), a potent and selective dopamine D(4) receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of L-745,870 in combination with L-DOPA. To guarantee D(4) selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of L-745,870. Coadministration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with L-DOPA alone (P < 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (-56%; P < 0.01). Brain levels of L-745,870 (∼600 ng/g) were within the range at which L-745,870 provides selective D(4) receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D(4) receptor antagonists represent a potential therapeutic approach for L-DOPA-induced dyskinesia. It is noteworthy that L-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">22619253</PMID><DateCreated><Year>2012</Year><Month>07</Month><Day>17</Day></DateCreated><DateCompleted><Year>2012</Year><Month>12</Month><Day>21</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1521-0103</ISSN><JournalIssue CitedMedium="Internet"><Volume>342</Volume><Issue>2</Issue><PubDate><Year>2012</Year><Month>Aug</Month></PubDate></JournalIssue><Title>The Journal of pharmacology and experimental therapeutics</Title><ISOAbbreviation>J. Pharmacol. Exp. Ther.</ISOAbbreviation></Journal><ArticleTitle>L-745,870 reduces L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>576-85</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1124/jpet.112.195693</ELocationID><Abstract><AbstractText>L-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (L-745,870), a potent and selective dopamine D(4) receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of L-745,870 in combination with L-DOPA. To guarantee D(4) selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of L-745,870. Coadministration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with L-DOPA alone (P < 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (-56%; P < 0.01). Brain levels of L-745,870 (∼600 ng/g) were within the range at which L-745,870 provides selective D(4) receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D(4) receptor antagonists represent a potential therapeutic approach for L-DOPA-induced dyskinesia. It is noteworthy that L-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Huot</LastName><ForeName>Philippe</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Johnston</LastName><ForeName>Tom H</ForeName><Initials>TH</Initials></Author><Author ValidYN="Y"><LastName>Koprich</LastName><ForeName>James B</ForeName><Initials>JB</Initials></Author><Author ValidYN="Y"><LastName>Aman</LastName><ForeName>Ahmed</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Fox</LastName><ForeName>Susan H</ForeName><Initials>SH</Initials></Author><Author ValidYN="Y"><LastName>Brotchie</LastName><ForeName>Jonathan M</ForeName><Initials>JM</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Agency>Canadian Institutes of Health Research</Agency><Country>Canada</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>05</Month><Day>22</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Pharmacol Exp Ther</MedlineTA><NlmUniqueID>0376362</NlmUniqueID><ISSNLinking>0022-3565</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C099630">3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000978">Antiparkinson Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011725">Pyridines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011758">Pyrroles</NameOfSubstance></Chemical><Chemical><RegistryNumber>137750-34-6</RegistryNumber><NameOfSubstance UI="D050638">Receptors, Dopamine D4</NameOfSubstance></Chemical><Chemical><RegistryNumber>46627O600J</RegistryNumber><NameOfSubstance UI="D007980">Levodopa</NameOfSubstance></Chemical><Chemical><RegistryNumber>9P21XSP91P</RegistryNumber><NameOfSubstance UI="D015632">1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D015632" MajorTopicYN="N">1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000978" MajorTopicYN="N">Antiparkinson Agents</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000134" MajorTopicYN="N">cerebrospinal fluid</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001921" MajorTopicYN="N">Brain</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004347" MajorTopicYN="N">Drug Interactions</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020820" MajorTopicYN="N">Dyskinesias</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000134" MajorTopicYN="N">cerebrospinal fluid</QualifierName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007980" MajorTopicYN="N">Levodopa</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008251" MajorTopicYN="N">Macaca</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009043" MajorTopicYN="N">Motor Activity</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010300" MajorTopicYN="N">Parkinson Disease</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000134" MajorTopicYN="N">cerebrospinal fluid</QualifierName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011725" MajorTopicYN="N">Pyridines</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000134" MajorTopicYN="N">cerebrospinal fluid</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011758" MajorTopicYN="N">Pyrroles</DescriptorName><QualifierName UI="Q000097" MajorTopicYN="N">blood</QualifierName><QualifierName UI="Q000134" MajorTopicYN="N">cerebrospinal fluid</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D050638" MajorTopicYN="N">Receptors, Dopamine D4</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>5</Month><Day>24</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>5</Month><Day>24</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>12</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">22619253</ArticleId><ArticleId IdType="pii">jpet.112.195693</ArticleId><ArticleId 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