The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.

A C Bartolomeo, H Morris, J J Buccafusco, N Kille, S Rosenzweig-Lipson, M G Husbands, A L Sabb, M Abou-Gharbia, J A Moyer, C A Boast

Central Nervous System Research/Central Nervous System Medicinal Chemistry, Wyeth-Ayerst Research, Princeton, New Jersey, USA.

The Journal of pharmacology and experimental therapeutics 2000 Feb

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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 microliter/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.

Citation

A C Bartolomeo, H Morris, J J Buccafusco, N Kille, S Rosenzweig-Lipson, M G Husbands, A L Sabb, M Abou-Gharbia, J A Moyer, C A Boast. The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist. The Journal of pharmacology and experimental therapeutics. 2000 Feb;292(2):584-96