There is no effective treatment to face Alzheimer’s disease complexity.Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression.In this ...There is no effective treatment to face Alzheimer’s disease complexity.Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression.In this context,N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine(ASS234)has been tested achieving promising results.ASS234 has demonstrated to cross the blood-brain barrier in vivo,and a good in silico safety profile being less toxic than donepezil.Besides,ASS234 reversibly inhibits human acetyl-and butyryl-cholinesterase,and irreversibly inhibits human monoamine oxidase A and B.Moreover,this multitarget molecule has antioxidant and neuroprotective properties,and inhibitsΑβ1–42 andΑβ1–40 self-aggregation.Inquiring about the mechanism of action,several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site(Wnt)family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes.Finally,in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus,ameliorating scopolamine-induced learning deficits.Here we gather the information regarding ASS234 evaluated so far,showing its ability to face different targets,necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease.展开更多
We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of ...We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.展开更多
文摘There is no effective treatment to face Alzheimer’s disease complexity.Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression.In this context,N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine(ASS234)has been tested achieving promising results.ASS234 has demonstrated to cross the blood-brain barrier in vivo,and a good in silico safety profile being less toxic than donepezil.Besides,ASS234 reversibly inhibits human acetyl-and butyryl-cholinesterase,and irreversibly inhibits human monoamine oxidase A and B.Moreover,this multitarget molecule has antioxidant and neuroprotective properties,and inhibitsΑβ1–42 andΑβ1–40 self-aggregation.Inquiring about the mechanism of action,several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site(Wnt)family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes.Finally,in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus,ameliorating scopolamine-induced learning deficits.Here we gather the information regarding ASS234 evaluated so far,showing its ability to face different targets,necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease.
基金MINECO(Government of Spain,grant number SAF-2015-65586-R)UCJC(grants"OPTICOMC903"and"NACONT")to JMC+2 种基金ARRS(Slovenian Research Agency)core research funding P1-0208,P4-0127 and P1-0189,and project Z1-1859Italian Ministry of Education,University and Research(MIUR,"Dipartimenti di Eccellenza Program 2018-2022-Dept.of Biology and Biotechnology L.Spallanzani",University of Pavia,Italy)the French Ministry of Armed Forces(Direction Générale des Armées and Service de Santédes Armées,France)under grant number NBC-5-C-4210。
文摘We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.
