CHF2819 is a novel orally active
acetylcholinesterase inhibitor (AChEI) developed for the treatment of
Alzheimer's disease (AD).
CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this
enzyme than against
butyrylcholinesterase (BuChE). Moreover,
CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo
CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased
acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this
neurotransmitter after administration of
CHF2819. At 1.5 mg/kg p.o.
CHF2819 attenuated
scopolamine-induced
amnesia in a passive avoidance task. Furthermore, it decreased
dopamine (DA) levels and increased extracellular levels of
5-hydroxytryptamine (5-HT) in the hippocampus, without modifying
norepinephrine (NE) levels. By
oral administration to young adult rats
CHF2819 did not affect extracellular hippocampal levels of
glutamate (Glu),
aspartate (Asp),
gamma-aminobutyric acid (
GABA),
taurine (Tau),
arginine (Arg) or
citrulline (
Cit). Functional observational battery (FOB) screening demonstrated that
CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (
body weight and temperature).
CHF2819 induced, however, involuntary motor movements (ranging from mild
tremors to
myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of
CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of
Alzheimer-type dementia associated with multiple
neurotransmitter abnormalities in the brain. In particular,
CHF2819 might be a useful therapeutic
drug for AD patients with
cognitive impairment accompanied by depression.