Lopez-Munoz F

References (8)

Title : 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases - Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
Author(s) : Knez D , Diez-Iriepa D , Chioua M , Gottinger A , Denic M , Chantegreil F , Nachon F , Brazzolotto X , Skrzypczak-Wiercioch A , Meden A , Pislar A , Kos J , Zakelj S , Stojan J , Salat K , Serrano J , Patricia Fernandez AP , Sanchez-Garcia A , Martinez-Murillo R , Binda C , Lopez-Munoz F , Gobec S , Marco-Contelle J
Ref : Acta Pharmaceutica Sinica B , 13 :2152 , 2023
Abstract : We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase -hBChE) 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 hBChE (IC50 = 1.06 +/- 0.31 nmol/L) and hMAO-B (IC50 = 4.46 +/- 0.18 micromol/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-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19
ESTHER : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedSearch : Knez_2023_Acta.Pharmaceutica.Sinica.B_13_2152
PubMedID: 37250172
Gene_locus related to this paper: human-BCHE

Title : The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents - Keuler_2022_ACS.Pharmacol.Transl.Sci_5_1097
Author(s) : Keuler T , Lemke C , Elsinghorst PW , Iriepa I , Chioua M , Martinez-Grau MA , Beadle CD , Vetman T , Lopez-Munoz F , Wille T , Bartz U , Deuther-Conrad W , Marco-Contelles J , Gutschow M
Ref : ACS Pharmacol Transl Sci , 5 :1097 , 2022
Abstract : The multifactorial nature of Alzheimer's disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized, and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the (1) and (2) receptors. Our study provides a framework for the development of further chromanone-based multineurotarget agents.
ESTHER : Keuler_2022_ACS.Pharmacol.Transl.Sci_5_1097
PubMedSearch : Keuler_2022_ACS.Pharmacol.Transl.Sci_5_1097
PubMedID: 36407962

Title : Polyfunctionalized alpha-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment - Diez-Iriepa_2022_Antioxidants.(Basel)_11_
Author(s) : Diez-Iriepa D , Knez D , Gobec S , Iriepa I , de los Rios C , Bravo I , Lopez-Munoz F , Marco-Contelles J , Hadjipavlou-Litina D
Ref : Antioxidants (Basel) , 11 : , 2022
Abstract : Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized alpha-phenyl-tert-butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS(+)-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of beta-amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide (5) was found to be one of the most potent antioxidants, with high ABTS(+) scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC(50) = 10 microM), selectively inhibiting butyrylcholinesterase (IC(50) = 3.46 +/- 0.27 microM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player.
ESTHER : Diez-Iriepa_2022_Antioxidants.(Basel)_11_
PubMedSearch : Diez-Iriepa_2022_Antioxidants.(Basel)_11_
PubMedID: 36139811

Title : Studies on the affinity of 6-[(n-(cyclo)aminoalkyl)oxy]-4H-chromen-4-ones for sigma 1\/2 receptors - Deuther-Conrad_2021_RSC.Med.Chem_12_1000
Author(s) : Deuther-Conrad W , Diez-Iriepa D , Iriepa I , Lopez-Munoz F , Martinez-Grau MA , Gutschow M , Marco-Contelles J
Ref : RSC Med Chem , 12 :1000 , 2021
Abstract : Sigma (sigma) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine sigma(1)/sigma(2) ligands. 6-(4-(Piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited sigma(1)/sigma(2) affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a K (i) value for sigma(1) of 27.2 nM (selectivity (sigma(1)/sigma(2)) = 28), combining the desired sigma(1) receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4H-chromen-4-one (12) was almost equipotent to S1RA, an established sigma(1) receptor antagonist.
ESTHER : Deuther-Conrad_2021_RSC.Med.Chem_12_1000
PubMedSearch : Deuther-Conrad_2021_RSC.Med.Chem_12_1000
PubMedID: 34223165

Title : Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy - Bautista-Aguilera_2020_Int.J.Mol.Sci_21_
Author(s) : Bautista-Aguilera OM , Ismaili L , Chioua M , Andrys R , Schmidt M , Bzonek P , Martinez-Grau MA , Beadle CD , Vetman T , Lopez-Munoz F , Iriepa I , Refouvelet B , Musilek K , Marco-Contelles J
Ref : Int J Mol Sci , 21 : , 2020
Abstract : In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 microM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
ESTHER : Bautista-Aguilera_2020_Int.J.Mol.Sci_21_
PubMedSearch : Bautista-Aguilera_2020_Int.J.Mol.Sci_21_
PubMedID: 32486316

Title : Contilisant, a Tetratarget Small Molecule for Alzheimer's Disease Therapy Combining Cholinesterase, Monoamine Oxidase Inhibition, and H3R Antagonism with S1R Agonism Profile - Bautista-Aguilera_2018_J.Med.Chem_61_6937
Author(s) : Bautista-Aguilera OM , Budni J , Mina F , Medeiros EB , Deuther-Conrad W , Entrena JM , Moraleda I , Iriepa I , Lopez-Munoz F , Marco-Contelles J
Ref : Journal of Medicinal Chemistry , 61 :6937 , 2018
Abstract : Contilisant, a permeable, antioxidant, and neuroprotectant agent, showing high nM affinity at H3R and excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective S1R agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecular modeling. In addition, contilisant significantly restores the cognitive deficit induced by Abeta1-42 in the radial maze assay in an in vivo Alzheimer's disease test, comparing very favorably with donepezil.
ESTHER : Bautista-Aguilera_2018_J.Med.Chem_61_6937
PubMedSearch : Bautista-Aguilera_2018_J.Med.Chem_61_6937
PubMedID: 29969030

Title : Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases - Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
Author(s) : Bautista-Aguilera OM , Hagenow S , Palomino-Antolin A , Farre-Alins V , Ismaili L , Joffrin PL , Jimeno ML , Soukup O , Janockova J , Kalinowsky L , Proschak E , Iriepa I , Moraleda I , Schwed JS , Romero Martinez A , Lopez-Munoz F , Chioua M , Egea J , Ramsay RR , Marco-Contelles J , Stark H
Ref : Angew Chem Int Ed Engl , 56 :12765 , 2017
Abstract : The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg(-1) i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
ESTHER : Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
PubMedSearch : Bautista-Aguilera_2017_Angew.Chem.Int.Ed.Engl_56_12765
PubMedID: 28861918

Title : [The development of neurotoxic agents as chemical weapons during the National Socialist period in Germany] - Lopez-Munoz_2008_Rev.Neurol_47_99
Author(s) : Lopez-Munoz F , Alamo C , Guerra JA , Garcia-Garcia P
Ref : Rev Neurol , 47 :99 , 2008
Abstract : INTRODUCTION: The discovery and development of the so-called 'nerve agents' (neurotoxic substances to be used as weapons) took place in the Third Reich, largely thanks to the vast amount of progress being made in pharmacology in Germany at that time, both in academic and industrial terms. Furthermore, successive National Socialist governments set up a collaborative network made up of the academia, the chemical industry and military chiefs that also favoured this line of research. DEVELOPMENT: The first neurotoxic substance to be incorporated into the category of 'chemical warfare agent' did so almost wholly by chance. As part of the work being carried out on organophosphate-type pesticides and insecticides, Gerald Schrader, a chemist at the I.G. Farben company, synthesised tabun (ethyl N,N-dimethylphosphoramidocyanidate) and an incident involving accidental contamination of laboratory staff with this substance highlighted its potential toxicity. The same group of researchers later synthesised another substance with the same properties, sarin (isopropyl methylphosphonofluoridate). Both agents were studied for use as chemical weapons by Wolfgang Wirth. At the same time, a group led by Richard Kuhn, who won the Nobel Prize in Chemistry in 1938, synthesised pinacolyl methylphosphonofluoridate, otherwise known as soman.
CONCLUSIONS: Pharmacological studies confirmed that the neurotoxic mechanism of action of these substances was the irreversible inhibition of the enzyme acetylcholinesterase, which is responsible for metabolising acetylcholine. Results also showed that an excess of this neurotransmitter led to a continuous over-stimulation of the cholinergic (nicotinic and muscarinic) receptors, which is what triggers the appearance of the wide range of symptoms of poisoning and their swift fatal effect.
ESTHER : Lopez-Munoz_2008_Rev.Neurol_47_99
PubMedSearch : Lopez-Munoz_2008_Rev.Neurol_47_99
PubMedID: 18623009