Abstract

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i.p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 μl/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.