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

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.

• Authors: 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
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 292 Issue 2 Pg. 584-96 (Feb 2000) ISSN: 0022-3565 [Print] United States
• PMID: 10640295 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aziridines
• Bridged-Ring Compounds
• Muscarinic Agonists
• Neuromuscular Blocking Agents
• Pyrazines
• Pyridines
• Thiadiazoles
• WAY 132983
• xanomeline
• ethylcholine aziridinium
• Scopolamine
• Choline O-Acetyltransferase
• Choline

Topics

• Animals
• Aziridines (pharmacology)
• Behavior, Animal (drug effects)
• Brain (metabolism)
• Bridged-Ring Compounds (administration & dosage, pharmacology, toxicity)
• Choline (analogs & derivatives, pharmacology)
• Choline O-Acetyltransferase (metabolism)
• Cognition (drug effects)
• Dose-Response Relationship, Drug
• Drug Interactions
• Female
• Frontal Lobe (drug effects, metabolism)
• Hippocampus (metabolism)
• Hypothermia (chemically induced)
• Macaca mulatta
• Male
• Mice
• Muscarinic Agonists (administration & dosage, pharmacology, toxicity)
• Neuromuscular Blocking Agents (pharmacology)
• Pyrazines (administration & dosage, pharmacology, toxicity)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Salivation (drug effects)
• Scopolamine (pharmacology)
• Thiadiazoles (pharmacology)
• Time Factors
• Visual Cortex (drug effects, metabolism)