The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.
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.
Bartolomeo
A C
AC
Central Nervous System Research/Central Nervous System Medicinal Chemistry, Wyeth-Ayerst Research, Princeton, New Jersey, USA.
Morris
H
H
Buccafusco
J J
JJ
Kille
N
N
Rosenzweig-Lipson
S
S
Husbands
M G
MG
Sabb
A L
AL
Abou-Gharbia
M
M
Moyer
J A
JA
Boast
C A
CA
D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002794:Choline / Q000031:analogs & derivatives / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012472:Salivation / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D013997:Time Factors; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
D001388:Aziridines; D001952:Bridged-Ring Compounds; D018721:Muscarinic Agonists; D009466:Neuromuscular Blocking Agents; D011719:Pyrazines; D011725:Pyridines; D013830:Thiadiazoles; C121282:WAY 132983; C075257:xanomeline; C044894:ethylcholine aziridinium; D012601:Scopolamine; D002795:Choline O-Acetyltransferase; D002794:Choline