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

Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (L-Dopa)-induced dyskinesias (LID). This study investigated the novel selective alpha 7 nAChR partial agonist (R)-3-(6-rho-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 alpha 7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of L-Dopa. (C) 2014 Elsevier Ltd. All rights reserved.