Inhibition of brain acetylcholinesterase (AChE) can provide relief fro
m the cognitive loss associated with Alzheimer's disease (AD). However
, unwanted peripheral side effects often limit the usefulness of the a
vailable anticholinesterases. Recently, we identified a dihydroquinazo
line compound, PD 142676 (CI 1002) that is a potent anticholinesterase
and a functional muscarinic antagonist at higher concentrations. Peri
pherally, PD 142676, unlike other anticholinesterases, inhibits gastro
intestinal motility in rats, an effect consistent with its muscarinic
antagonist properties. Centrally, the compound acts as a cholinomimeti
c. In rats, PD 142676 decreases core body temperature. It also increas
es neocortical arousal, as measured by quantitative electroencephalogr
aphy, and cortical acetylcholine levels, measured by in vivo microdial
ysis. The compound improves the performance of C57/B10j mice in a wate
r maze task and of aged rhesus monkeys in a delayed match-to-sample ta
sk involving short-term memory. The combined effect of AChE inhibition
and muscarinic antagonism distinguishes PD 142676 from other antichol
inesterases, and may be useful in treating the cognitive dysfunction o
f AD and produce fewer peripheral side effects.