Bartolomeo_2000_J.Pharmacol.Exp.Ther_292_584

Reference

Title : The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist - Bartolomeo_2000_J.Pharmacol.Exp.Ther_292_584
Author(s) : Bartolomeo AC , Morris H , Buccafusco JJ , Kille N , Rosenzweig-Lipson S , Husbands MG , Sabb AL , Abou-Gharbia M , Moyer JA , Boast CA
Ref : Journal of Pharmacology & Experimental Therapeutics , 292 :584 , 2000
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 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.

PubMedSearch : Bartolomeo_2000_J.Pharmacol.Exp.Ther_292_584
PubMedID: 10640295

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Citations formats

Bartolomeo AC, Morris H, Buccafusco JJ, Kille N, Rosenzweig-Lipson S, Husbands MG, Sabb AL, Abou-Gharbia M, Moyer JA, Boast CA (2000)
The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist
Journal of Pharmacology & Experimental Therapeutics 292 :584

Bartolomeo AC, Morris H, Buccafusco JJ, Kille N, Rosenzweig-Lipson S, Husbands MG, Sabb AL, Abou-Gharbia M, Moyer JA, Boast CA (2000)
Journal of Pharmacology & Experimental Therapeutics 292 :584