AQW051, a novel and selective nicotinic acetylcholine receptor α7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys.
Identifieur interne : 000B60 ( Main/Exploration ); précédent : 000B59; suivant : 000B61AQW051, a novel and selective nicotinic acetylcholine receptor α7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys.
Auteurs : Thérèse Di Paolo [Canada] ; Laurent Grégoire [Canada] ; Dominik Feuerbach [Canada] ; Walid Elbast [Canada] ; Markus Weiss [Canada] ; Baltazar Gomez-Mancilla [Canada]Source :
- Parkinsonism & related disorders [ 1873-5126 ] ; 2014.
English descriptors
- KwdEn :
- Analysis of Variance, Animals, Antiparkinson Agents (adverse effects), Disease Models, Animal, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced (drug therapy), Dyskinesia, Drug-Induced (etiology), Female, Levodopa (adverse effects), MPTP Poisoning (drug therapy), Macaca fascicularis, Motor Activity (drug effects), Nicotinic Agonists (therapeutic use), Ovariectomy, Time Factors, alpha7 Nicotinic Acetylcholine Receptor (agonists).
- MESH :
- chemical , adverse effects : Antiparkinson Agents, Levodopa.
- chemical , agonists : alpha7 Nicotinic Acetylcholine Receptor.
- drug effects : Motor Activity.
- drug therapy : Dyskinesia, Drug-Induced, MPTP Poisoning.
- etiology : Dyskinesia, Drug-Induced.
- chemical , therapeutic use : Nicotinic Agonists.
- Analysis of Variance, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Macaca fascicularis, Ovariectomy, Time Factors.
Abstract
Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15 mg/kg) administered 1 h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15 mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1 h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15 mg/kg). To understand the exposure-effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15 mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa.
DOI: 10.1016/j.parkreldis.2014.05.007
PubMed: 25172125
Affiliations:
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Faculty of Pharmacy, Laval University, Quebec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author><author><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Grégoire">Laurent Grégoire</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author><author><name sortKey="Feuerbach, Dominik" sort="Feuerbach, Dominik" uniqKey="Feuerbach D" first="Dominik" last="Feuerbach">Dominik Feuerbach</name><affiliation wicri:level="4"><nlm:affiliation>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Elbast, Walid" sort="Elbast, Walid" uniqKey="Elbast W" first="Walid" last="Elbast">Walid Elbast</name><affiliation wicri:level="4"><nlm:affiliation>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Weiss, Markus" sort="Weiss, Markus" uniqKey="Weiss M" first="Markus" last="Weiss">Markus Weiss</name><affiliation wicri:level="4"><nlm:affiliation>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Gomez Mancilla, Baltazar" sort="Gomez Mancilla, Baltazar" uniqKey="Gomez Mancilla B" first="Baltazar" last="Gomez-Mancilla">Baltazar Gomez-Mancilla</name><affiliation wicri:level="4"><nlm:affiliation>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada. Electronic address: baltazar.gomezmancilla@novartis.com.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></analytic><series><title level="j">Parkinsonism & related disorders</title><idno type="eISSN">1873-5126</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Analysis of Variance</term><term>Animals</term><term>Antiparkinson Agents (adverse effects)</term><term>Disease Models, Animal</term><term>Dose-Response Relationship, Drug</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>Macaca fascicularis</term><term>Motor Activity (drug effects)</term><term>Nicotinic Agonists (therapeutic use)</term><term>Ovariectomy</term><term>Time Factors</term><term>alpha7 Nicotinic Acetylcholine Receptor (agonists)</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="agonists" xml:lang="en"><term>alpha7 Nicotinic Acetylcholine Receptor</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Motor Activity</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>MPTP Poisoning</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Nicotinic Agonists</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Analysis of Variance</term><term>Animals</term><term>Disease Models, Animal</term><term>Dose-Response Relationship, Drug</term><term>Female</term><term>Macaca fascicularis</term><term>Ovariectomy</term><term>Time Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15 mg/kg) administered 1 h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15 mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1 h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15 mg/kg). To understand the exposure-effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15 mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name></noRegion><name sortKey="Elbast, Walid" sort="Elbast, Walid" uniqKey="Elbast W" first="Walid" last="Elbast">Walid Elbast</name><name sortKey="Feuerbach, Dominik" sort="Feuerbach, Dominik" uniqKey="Feuerbach D" first="Dominik" last="Feuerbach">Dominik Feuerbach</name><name sortKey="Gomez Mancilla, Baltazar" sort="Gomez Mancilla, Baltazar" uniqKey="Gomez Mancilla B" first="Baltazar" last="Gomez-Mancilla">Baltazar Gomez-Mancilla</name><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Grégoire">Laurent Grégoire</name><name sortKey="Weiss, Markus" sort="Weiss, Markus" uniqKey="Weiss M" first="Markus" last="Weiss">Markus Weiss</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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