The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques.
Identifieur interne : 001353 ( Ncbi/Curation ); précédent : 001352; suivant : 001354The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques.
Auteurs : James B. Koprich [Canada] ; Philippe Huot ; Susan H. Fox ; Keith Jarvie ; Anthony E. Lang ; Philip Seeman ; Jonathan M. BrotchieSource :
- Progress in neuro-psychopharmacology & biological psychiatry [ 1878-4216 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Antiparkinson Agents (adverse effects), Behavior, Animal (drug effects), Butyrophenones (pharmacology), Cloning, Molecular, Dopamine Antagonists (pharmacology), Dopamine D2 Receptor Antagonists, Dyskinesia, Drug-Induced (drug therapy), Dyskinesia, Drug-Induced (etiology), Female, Levodopa (adverse effects), MPTP Poisoning (drug therapy), MPTP Poisoning (psychology), Macaca fascicularis, Male, Parkinson Disease, Secondary (complications), Parkinson Disease, Secondary (drug therapy), Psychoses, Substance-Induced (drug therapy), Psychoses, Substance-Induced (etiology).
- MESH :
- chemical , adverse effects : Antiparkinson Agents, Levodopa.
- complications : Parkinson Disease, Secondary.
- drug effects : Behavior, Animal.
- drug therapy : Dyskinesia, Drug-Induced, MPTP Poisoning, Parkinson Disease, Secondary, Psychoses, Substance-Induced.
- etiology : Dyskinesia, Drug-Induced, Psychoses, Substance-Induced.
- chemical , pharmacology : Butyrophenones, Dopamine Antagonists.
- psychology : MPTP Poisoning.
- Animals, Cloning, Molecular, Dopamine D2 Receptor Antagonists, Female, Macaca fascicularis, Male.
Abstract
3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.
DOI: 10.1016/j.pnpbp.2012.12.008
PubMed: 23306217
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Koprich</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8.</nlm:affiliation><country>Canada</country><wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Huot, Philippe" sort="Huot, Philippe" uniqKey="Huot P" first="Philippe" last="Huot">Philippe Huot</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="Jarvie, Keith" sort="Jarvie, Keith" uniqKey="Jarvie K" first="Keith" last="Jarvie">Keith Jarvie</name></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. 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Koprich</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8.</nlm:affiliation><country>Canada</country><wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Huot, Philippe" sort="Huot, Philippe" uniqKey="Huot P" first="Philippe" last="Huot">Philippe Huot</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="Jarvie, Keith" sort="Jarvie, Keith" uniqKey="Jarvie K" first="Keith" last="Jarvie">Keith Jarvie</name></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E" last="Lang">Anthony E. Lang</name></author><author><name sortKey="Seeman, Philip" sort="Seeman, Philip" uniqKey="Seeman P" first="Philip" last="Seeman">Philip Seeman</name></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name></author></analytic><series><title level="j">Progress in neuro-psychopharmacology & biological psychiatry</title><idno type="eISSN">1878-4216</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiparkinson Agents (adverse effects)</term><term>Behavior, Animal (drug effects)</term><term>Butyrophenones (pharmacology)</term><term>Cloning, Molecular</term><term>Dopamine Antagonists (pharmacology)</term><term>Dopamine D2 Receptor Antagonists</term><term>Dyskinesia, Drug-Induced (drug therapy)</term><term>Dyskinesia, Drug-Induced (etiology)</term><term>Female</term><term>Levodopa (adverse effects)</term><term>MPTP Poisoning (drug therapy)</term><term>MPTP Poisoning (psychology)</term><term>Macaca fascicularis</term><term>Male</term><term>Parkinson Disease, Secondary (complications)</term><term>Parkinson Disease, Secondary (drug therapy)</term><term>Psychoses, Substance-Induced (drug therapy)</term><term>Psychoses, Substance-Induced (etiology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Antiparkinson Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Behavior, Animal</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>MPTP Poisoning</term><term>Parkinson Disease, Secondary</term><term>Psychoses, Substance-Induced</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Psychoses, Substance-Induced</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Butyrophenones</term><term>Dopamine Antagonists</term></keywords><keywords scheme="MESH" qualifier="psychology" xml:lang="en"><term>MPTP Poisoning</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cloning, Molecular</term><term>Dopamine D2 Receptor Antagonists</term><term>Female</term><term>Macaca fascicularis</term><term>Male</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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