6533b7defe1ef96bd127694b
RESEARCH PRODUCT
(±)- BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease
Vendula HepnarovaKamil MusilekAurélie BaguetDaniel JunJosé Marco-contellesLhassane IsmailiEmmanuel HaffenTomas KuceraJan KorabecnyJana JanockovaAngela De SimoneEva M. García-frutosVincenza AndrisanoManuela BartoliniB. RefouveletLucía ViejoCristóbal De Los RíosAdeline EtievantOndrej SoukupRudolf AndrysJulie MonninRaquel L Arribassubject
cholinesterasePhysiologyMonoamine oxidaseCognitive NeuroscienceLigandPharmacologyLigandsCalcium ChannelBiochemistry03 medical and health sciences0302 clinical medicineAlzheimer DiseaseIn vivoGSK-3HumansCholinesterasesCholinesterase InhibitorBiginelli reactionAlzheimer's disease; Biginelli reaction; calcium channel; cholinesterases; GSK 3β; MAO; Calcium Channel Blockers; Calcium Channels; Cholinesterase Inhibitors; Glycogen Synthase Kinase 3 beta; Humans; Ligands; Monoamine Oxidase; Alzheimer DiseaseMonoamine OxidaseGSK3B030304 developmental biologyCholinesterase0303 health sciencesGlycogen Synthase Kinase 3 betaVoltage-dependent calcium channelbiologyChemistryCalcium channelCell BiologyGeneral MedicineAlzheimer's diseaseCalcium Channel BlockersCalcium channel GSK 3β MAOMAObiology.proteinCalcium ChannelsCholinesterase InhibitorsGSK 3βMonoamine oxidase ACalcium Channel BlockerAlzheimer’s disease030217 neurology & neurosurgeryHumandescription
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-04-02 |