Vol. 292, Issue 2, 584-596, February 2000

The Preclinical Pharmacological Profile of WAY-132983, a Potent M1 Preferring Agonist¹

Adam C. Bartolomeo, Herman Morris, Jerry J. Buccafusco , Nancy Kille , Sharon Rosenzweig-Lipson, Morris G. Husbands, Annmarie L. Sabb, Magid Abou-Gharbia, John A. Moyer and Carl A. Boast

Central Nervous System Research/Central Nervous System Medicinal Chemistry, Wyeth-Ayerst Research, Princeton, New Jersey (A.C.B., H.M., S.R.-L., M.G.H., A.L.S., M.A.-G., J.A.M., C.A.B.); Alzheimer's Research Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia (J.J.B., N.K.); and the Veterans Administration Medical Center, Augusta, Georgia (J.J.B., N.K.).

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.