Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inh...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-05, Vol.52 (9), p.2724-2732
Hauptverfasser:	Marco-Contelles, José, León, Rafael, de los Ríos, Cristóbal, Samadi, Abdelouahid, Bartolini, Manuela, Andrisano, Vincenza, Huertas, Oscar, Barril, Xavier, Luque, F. Javier, Rodríguez-Franco, María I, López, Beatriz, López, Manuela G, García, Antonio G, do Carmo Carreiras, María, Villarroya, Mercedes
Format:	Artikel
Sprache:	eng
Schlagworte:	Acetylcholinesterase - metabolism Alzheimer Disease - drug therapy Alzheimer Disease - enzymology Alzheimer Disease - metabolism Alzheimer Disease - pathology Amyloid beta-Peptides - metabolism Biological and medical sciences Blood-Brain Barrier - drug effects Blood-Brain Barrier - metabolism Butyrylcholinesterase - metabolism Calcium - metabolism Calcium Channel Blockers - chemistry Calcium Channel Blockers - metabolism Calcium Channel Blockers - pharmacology Calcium Channel Blockers - therapeutic use Catalytic Domain Cell Death - drug effects Cell Line, Tumor Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - metabolism Cholinesterase Inhibitors - pharmacology Cholinesterase Inhibitors - therapeutic use Cytosol - drug effects Cytosol - metabolism Dihydropyridines - chemistry Dihydropyridines - metabolism Dihydropyridines - pharmacology Dihydropyridines - therapeutic use Humans Hydrogen Peroxide - metabolism Kinetics Ligands Medical sciences Models, Molecular Neuropharmacology Neuroprotective agent Peptide Fragments - metabolism Permeability - drug effects Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Tacrine - analogs & derivatives
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container_title	Journal of medicinal chemistry
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creator	Marco-Contelles, José León, Rafael de los Ríos, Cristóbal Samadi, Abdelouahid Bartolini, Manuela Andrisano, Vincenza Huertas, Oscar Barril, Xavier Luque, F. Javier Rodríguez-Franco, María I López, Beatriz López, Manuela G García, Antonio G do Carmo Carreiras, María Villarroya, Mercedes
description	Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.
doi_str_mv	10.1021/jm801292b
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Javier ; Rodríguez-Franco, María I ; López, Beatriz ; López, Manuela G ; García, Antonio G ; do Carmo Carreiras, María ; Villarroya, Mercedes</creator><creatorcontrib>Marco-Contelles, José ; León, Rafael ; de los Ríos, Cristóbal ; Samadi, Abdelouahid ; Bartolini, Manuela ; Andrisano, Vincenza ; Huertas, Oscar ; Barril, Xavier ; Luque, F. Javier ; Rodríguez-Franco, María I ; López, Beatriz ; López, Manuela G ; García, Antonio G ; do Carmo Carreiras, María ; Villarroya, Mercedes</creatorcontrib><description>Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm801292b</identifier><identifier>PMID: 19374444</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Acetylcholinesterase - metabolism ; Alzheimer Disease - drug therapy ; Alzheimer Disease - enzymology ; Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Amyloid beta-Peptides - metabolism ; Biological and medical sciences ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Butyrylcholinesterase - metabolism ; Calcium - metabolism ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - metabolism ; Calcium Channel Blockers - pharmacology ; Calcium Channel Blockers - therapeutic use ; Catalytic Domain ; Cell Death - drug effects ; Cell Line, Tumor ; Cholinesterase Inhibitors - chemistry ; Cholinesterase Inhibitors - metabolism ; Cholinesterase Inhibitors - pharmacology ; Cholinesterase Inhibitors - therapeutic use ; Cytosol - drug effects ; Cytosol - metabolism ; Dihydropyridines - chemistry ; Dihydropyridines - metabolism ; Dihydropyridines - pharmacology ; Dihydropyridines - therapeutic use ; Humans ; Hydrogen Peroxide - metabolism ; Kinetics ; Ligands ; Medical sciences ; Models, Molecular ; Neuropharmacology ; Neuroprotective agent ; Peptide Fragments - metabolism ; Permeability - drug effects ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. 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Javier</creatorcontrib><creatorcontrib>Rodríguez-Franco, María I</creatorcontrib><creatorcontrib>López, Beatriz</creatorcontrib><creatorcontrib>López, Manuela G</creatorcontrib><creatorcontrib>García, Antonio G</creatorcontrib><creatorcontrib>do Carmo Carreiras, María</creatorcontrib><creatorcontrib>Villarroya, Mercedes</creatorcontrib><title>Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.</description><subject>Acetylcholinesterase - metabolism</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - enzymology</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Butyrylcholinesterase - metabolism</subject><subject>Calcium - metabolism</subject><subject>Calcium Channel Blockers - chemistry</subject><subject>Calcium Channel Blockers - metabolism</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Calcium Channel Blockers - therapeutic use</subject><subject>Catalytic Domain</subject><subject>Cell Death - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cholinesterase Inhibitors - chemistry</subject><subject>Cholinesterase Inhibitors - metabolism</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cholinesterase Inhibitors - therapeutic use</subject><subject>Cytosol - drug effects</subject><subject>Cytosol - metabolism</subject><subject>Dihydropyridines - chemistry</subject><subject>Dihydropyridines - metabolism</subject><subject>Dihydropyridines - pharmacology</subject><subject>Dihydropyridines - therapeutic use</subject><subject>Humans</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Neuroprotective agent</subject><subject>Peptide Fragments - metabolism</subject><subject>Permeability - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Tacrine - analogs & derivatives</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0D1vFDEQBmALgchxUPAHkBuQkFiwx96vMsoRgnSI5qhXXnuc82k_Do-3OCoapNTp-Hv5JWySU9LgZqzRo3ekl7HXUnyUAuSnXV8JCTW0T9hC5iAyXQn9lC2EAMigAHXCXhDthBBKgnrOTmStSj2_BfuzMTaG_SGGAekDT1vk5yFS4nf7AW-urldhe3BxvDVu3vCLQzv_ZmyIf5u6FJKJl5iyVYhoEzq-DpdmcMT9GO8CNxFN6nFIfPT8tPu1xdBjvPn9l_gqEBrCl-yZNx3hq-Ncsh_nnzdnF9n6-5evZ6frzGhRp6yAWijlvKyMkLkEk0tspYe6VmigMNIJ37bW67r0DlzVFrpytsyVAqgK0GrJ3t3n7uP4c0JKTR_IYteZAceJmqIEpfR8Y8ne30MbR6KIvtnH0Jt4aKRobjtvHjqf7Ztj6NT26B7lseQZvD0CQ9Z0PprBBnpwIHVd5KV4dMZSsxunOMxd_OfgP9_4mEE</recordid><startdate>20090514</startdate><enddate>20090514</enddate><creator>Marco-Contelles, José</creator><creator>León, Rafael</creator><creator>de los Ríos, Cristóbal</creator><creator>Samadi, Abdelouahid</creator><creator>Bartolini, Manuela</creator><creator>Andrisano, Vincenza</creator><creator>Huertas, Oscar</creator><creator>Barril, Xavier</creator><creator>Luque, F. Javier</creator><creator>Rodríguez-Franco, María I</creator><creator>López, Beatriz</creator><creator>López, Manuela G</creator><creator>García, Antonio G</creator><creator>do Carmo Carreiras, María</creator><creator>Villarroya, Mercedes</creator><general>American Chemical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20090514</creationdate><title>Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease</title><author>Marco-Contelles, José ; León, Rafael ; de los Ríos, Cristóbal ; Samadi, Abdelouahid ; Bartolini, Manuela ; Andrisano, Vincenza ; Huertas, Oscar ; Barril, Xavier ; Luque, F. Javier ; Rodríguez-Franco, María I ; López, Beatriz ; López, Manuela G ; García, Antonio G ; do Carmo Carreiras, María ; Villarroya, Mercedes</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a409t-629033df18a01512a51eb1f2993ea26a1d0fbbcf497fd2d8b648dc75332286243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Acetylcholinesterase - metabolism</topic><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - enzymology</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Butyrylcholinesterase - metabolism</topic><topic>Calcium - metabolism</topic><topic>Calcium Channel Blockers - chemistry</topic><topic>Calcium Channel Blockers - metabolism</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Calcium Channel Blockers - therapeutic use</topic><topic>Catalytic Domain</topic><topic>Cell Death - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cholinesterase Inhibitors - chemistry</topic><topic>Cholinesterase Inhibitors - metabolism</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cholinesterase Inhibitors - therapeutic use</topic><topic>Cytosol - drug effects</topic><topic>Cytosol - metabolism</topic><topic>Dihydropyridines - chemistry</topic><topic>Dihydropyridines - metabolism</topic><topic>Dihydropyridines - pharmacology</topic><topic>Dihydropyridines - therapeutic use</topic><topic>Humans</topic><topic>Hydrogen Peroxide - metabolism</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Neuropharmacology</topic><topic>Neuroprotective agent</topic><topic>Peptide Fragments - metabolism</topic><topic>Permeability - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Tacrine - analogs & derivatives</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marco-Contelles, José</creatorcontrib><creatorcontrib>León, Rafael</creatorcontrib><creatorcontrib>de los Ríos, Cristóbal</creatorcontrib><creatorcontrib>Samadi, Abdelouahid</creatorcontrib><creatorcontrib>Bartolini, Manuela</creatorcontrib><creatorcontrib>Andrisano, Vincenza</creatorcontrib><creatorcontrib>Huertas, Oscar</creatorcontrib><creatorcontrib>Barril, Xavier</creatorcontrib><creatorcontrib>Luque, F. 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Javier</au><au>Rodríguez-Franco, María I</au><au>López, Beatriz</au><au>López, Manuela G</au><au>García, Antonio G</au><au>do Carmo Carreiras, María</au><au>Villarroya, Mercedes</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-05-14</date><risdate>2009</risdate><volume>52</volume><issue>9</issue><spage>2724</spage><epage>2732</epage><pages>2724-2732</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19374444</pmid><doi>10.1021/jm801292b</doi><tpages>9</tpages></addata></record>
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subjects	Acetylcholinesterase - metabolism Alzheimer Disease - drug therapy Alzheimer Disease - enzymology Alzheimer Disease - metabolism Alzheimer Disease - pathology Amyloid beta-Peptides - metabolism Biological and medical sciences Blood-Brain Barrier - drug effects Blood-Brain Barrier - metabolism Butyrylcholinesterase - metabolism Calcium - metabolism Calcium Channel Blockers - chemistry Calcium Channel Blockers - metabolism Calcium Channel Blockers - pharmacology Calcium Channel Blockers - therapeutic use Catalytic Domain Cell Death - drug effects Cell Line, Tumor Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - metabolism Cholinesterase Inhibitors - pharmacology Cholinesterase Inhibitors - therapeutic use Cytosol - drug effects Cytosol - metabolism Dihydropyridines - chemistry Dihydropyridines - metabolism Dihydropyridines - pharmacology Dihydropyridines - therapeutic use Humans Hydrogen Peroxide - metabolism Kinetics Ligands Medical sciences Models, Molecular Neuropharmacology Neuroprotective agent Peptide Fragments - metabolism Permeability - drug effects Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Tacrine - analogs & derivatives
title	Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease
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