title: 1-[2-(4-Benzyloxyphenoxy)Ethyl]Imidazole inhibits monoamine oxidase B and protects against neuronal loss and behavioral impairment in rodent models of Parkinson's disease.
abstract: Monoamine oxidase B (MAO-B) is well known as a therapeutic target for Parkinson's disease (PD). MAO-B inhibitors retain antiparkinsonism abilities to improve motor function and prevent neuronal loss by decreasing dopamine metabolism and oxidative stress in the brain. From the study to find novel antiparkinsonism drugs that can inhibit MAO-B activity, neuronal loss, and behavioral deficits in the mouse model of PD, we identified that 1-[2-(4-benzyloxyphenoxy)ethyl]imidazole (BPEI) or safinamide strongly and selectively inhibited MAO-B activities in a dose-dependent manner (IC50 of BPEI and safinamide for MAO-B were 0.016 and 0.0021 µM and for MAO-A were 70.0 and 370 µM, respectively). In ex vivo studies after an administration (30 mg/kg, i.p.) of BPEI or safinamide to normal mice, the MAO-B activity in the brain was reduced by up to 90.6% or 82.4% at 1.0 hr. BPEI (20 mg/kg, i.p.) or safinamide (20 mg/kg, i.p.) significantly reversed the behavioral impairments, dopamine levels in the striatum, and neuronal loss in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice compared with the MPTP-alone-treated group. In the 6-hydroxydopamine-induced PD rat model, behavioral improvement by levodopa sparing activity was observed in the BPEI- or safinamide-treated (20 mg/kg, i.p.) rats. Moreover, BPEI revealed additional curative activities for nonmotor symptoms of PD such as pain, anxiety, epilepsy, and depression in rodent disease models. Therefore, BPEI has broad therapeutic potential for treating motor symptoms via strong and selective inhibitory effects on MAO-B, with additional benefits for comorbid symptoms in PD.
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Jin Yong
authors.initials: JY
authors.lastname: Chung
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Choon Ho
authors.initials: CH
authors.lastname: Ryu
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Min
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Yoon
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Lim
authors.affiliation: Drug Discovery Center, SK Biopharmaceuticals Ltd., Dae Jeon, South Korea.
authors.forename: Cheol Hyoung
authors.initials: CH
authors.lastname: Park
mesh_terms: D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007093:Imidazoles; D008996:Monoamine Oxidase Inhibitors; C029899:imidazole; D008995:Monoamine Oxidase
keywords: 1-[2-(4-benzyloxyphenoxy)ethyl]imidazole (BPEI); 6-OHDA; MAO-B inhibitor; MPTP; Parkinson's disease