Neurochemical profiles of UR-1827, a novel acetylcholinesterase inhibitor with inhibitory activities on both monoamine oxidase A and NE uptake

UR-1827 (1-[4-[(5-methyl-4-pyrimidinyl)amino]phenyl]-2-[1-(phenylmethyl)-4-piperidinyl]-ethanone) is a novel compound which possesses equipotent inhibitory activities on acetylcholinesterase (AChE), monoamine oxidase A (MAO-A) and NE uptake in vitro. IC_50 values were 0.25, 0.34 and 0.064μM, respectively. To elucidate neurochemical profiles of UR-1827, we investigated the ex vivo inhibition of AChE and MAO-A by UR-1827 in mouse and rat brain, and evaluated the effects of UR-1827 on extracellular levels of ACh, monoamines and their related metabolites in rat striatum using microdialysis method. In ex vivo studies, AChE and MAO-A activities in mouse and rat brain were inhibited dose-dependently by oral administration of UR-1827, and were recovered to pre-administration levels after 24 hours. ED_50 values for AChE and MAO-A were 16.4 and 16.0 mg/kg, p.o. in mice and 31.0 and 23.8 mg/kg, p.o. in rats, respectively. In microdialysis studies, the concentrations of ACh, DA and 3-MT in dialysates were increased, and the concentrations of DOPAG, HVA and 5-HIAA were decreased dose-dependently after oral administration of UR-1827 (25-100 mg/kg). These results suggest that UR-1827 enhances simultaneously both cholinergic and monoaminergic neurotransmission.