title: 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.
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.
authors.affiliation: Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC, Canada.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
authors.affiliation: Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec, QC, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada.
authors.forename: Walid
authors.initials: W
authors.lastname: Elbast
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, QC, Canada.
authors.forename: Markus
authors.initials: M
authors.lastname: Weiss
authors.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.
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D007980:Levodopa / Q000009:adverse effects*; D020267:MPTP Poisoning / Q000188:drug therapy*; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010052:Ovariectomy; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D000978:Antiparkinson Agents; D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007980:Levodopa
keywords: AQW051; Dyskinesia; MPTP monkey; Parkinson's disease; l-Dopa; α7 nicotinic acetylcholine receptor