Leon R

References (16)

Title : Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer's Disease - Michalska_2020_Antioxidants.(Basel)_9_
Author(s) : Michalska P , Mayo P , Fernandez-Mendivil C , Tenti G , Duarte P , Buendia I , Ramos MT , Lopez MG , Menendez JC , Leon R
Ref : Antioxidants (Basel) , 9 : , 2020
Abstract : Alzheimer's disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3beta, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca(2+) homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2H-pyrazolo[3-b]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3beta and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound 4g revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer's disease.
ESTHER : Michalska_2020_Antioxidants.(Basel)_9_
PubMedSearch : Michalska_2020_Antioxidants.(Basel)_9_
PubMedID: 32708053

Title : Antioxidant, Antimicrobial, and Bioactive Potential of Two New Haloarchaeal Strains Isolated from Odiel Salterns (Southwest Spain) - Gomez-Villegas_2020_Biology.(Basel)_9_
Author(s) : Gomez-Villegas P , Vigara J , Vila M , Varela J , Barreira L , Leon R
Ref : Biology (Basel) , 9 : , 2020
Abstract : The need to survive in extreme environments has furnished haloarchaea with a series of components specially adapted to work in such conditions. The possible application of these molecules in the pharmaceutical and industrial fields has received increasing attention; however, many potential bioactivities of haloarchaea are still poorly explored. In this paper, we describe the isolation and identification of two new haloarchaeal strains from the saltern ponds located in the marshlands of the Odiel River, in the southwest of Spain, as well as the in vitro assessment of their antioxidant, antimicrobial, and bioactive properties. The acetone extract obtained from the new isolated Haloarcula strain exhibited the highest antioxidant activity, while the acetone extracts from both isolated strains demonstrated a strong antimicrobial activity, especially against other halophilic microorganisms. Moreover, these extracts showed a remarkable ability to inhibit the enzyme cyclooxygenase-2 and to activate the melanogenic enzyme tyrosinase, indicating their potential against chronic inflammation and skin pigmentation disorders. Finally, the aqueous protein-rich extracts obtained from both haloarchaea exhibited an important inhibitory effect on the activity of the acetylcholinesterase enzyme, involved in the hydrolysis of cholinergic neurotransmitters and related to several neurological diseases.
ESTHER : Gomez-Villegas_2020_Biology.(Basel)_9_
PubMedSearch : Gomez-Villegas_2020_Biology.(Basel)_9_
PubMedID: 32962162

Title : Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia - Monjas_2017_Eur.J.Med.Chem_130_60
Author(s) : Monjas L , Arce MP , Leon R , Egea J , Perez C , Villarroya M , Lopez MG , Gil C , Conde S , Rodriguez-Franco MI
Ref : Eur Journal of Medicinal Chemistry , 130 :60 , 2017
Abstract : Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the alpha-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.
ESTHER : Monjas_2017_Eur.J.Med.Chem_130_60
PubMedSearch : Monjas_2017_Eur.J.Med.Chem_130_60
PubMedID: 28242552

Title : The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators - Benchekroun_2016_J.Med.Chem_59_9967
Author(s) : Benchekroun M , Romero A , Egea J , Leon R , Michalska P , Buendia I , Jimeno ML , Jun D , Janockova J , Sepsova V , Soukup O , Bautista-Aguilera OM , Refouvelet B , Ouari O , Marco-Contelles J , Ismaili L
Ref : Journal of Medicinal Chemistry , 59 :9967 , 2016
Abstract : Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.
ESTHER : Benchekroun_2016_J.Med.Chem_59_9967
PubMedSearch : Benchekroun_2016_J.Med.Chem_59_9967
PubMedID: 27736061

Title : Subthreshold Concentrations of Melatonin and Galantamine Improves Pathological AD-Hallmarks in Hippocampal Organotypic Cultures - Buendia_2016_Mol.Neurobiol_53_3338
Author(s) : Buendia I , Parada E , Navarro E , Leon R , Negredo P , Egea J , Lopez MG
Ref : Molecular Neurobiology , 53 :3338 , 2016
Abstract : Melatonin is a neurohormone whose levels are significantly reduced or absent in Alzheimer's disease (AD) patients. In these patients, acetylcholinesterase inhibitors (AChEI) are the major drug class used for their treatment; however, they present unwanted cholinergic side effects and have provided limited efficacy in clinic. Because combination therapy is being extensively used to treat different pathological diseases such as cancer or acquired immune deficiency syndrome, we posed this study to evaluate if melatonin in combination with an AChEI, galantamine, could provide beneficial properties in a novel in vitro model of AD. Thus, we subjected organotypic hippocampal cultures (OHCs) to subtoxic concentrations of beta-amyloid (0.5 muM betaA) plus okadaic acid (1 nM OA), for 4 days. This treatment increased by 95 % cell death, which was mainly apoptotic as shown by positive TUNEL staining. In addition, the combination of betaA/OA increased Thioflavin S aggregates, hyperphosphorylation of Tau, oxidative stress (increased DCFDA fluorescence), and neuroinflammation (increased IL-1beta and TNFalpha). Under these experimental conditions, melatonin (1-1000 nM) and galantamine (10-1000 nM), co-incubated with the toxic stimuli, caused a concentration-dependent neuroprotection; maximal neuroprotective effect was achieved at 1 muM of melatonin and galantamine. Most effective was the finding that combination of sub-effective concentrations of melatonin (1 nM) and galantamine (10 nM) provided a synergic anti-apoptotic effect and reduction of most of the AD-related pathological hallmarks observed in the betaA/OA model. Therefore, we suggest that supplementation of melatonin in combination with lower doses of AChEIs could be an interesting strategy for AD patients.
ESTHER : Buendia_2016_Mol.Neurobiol_53_3338
PubMedSearch : Buendia_2016_Mol.Neurobiol_53_3338
PubMedID: 26081146

Title : Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection - Egea_2015_Biochem.Pharmacol_97(4)_463
Author(s) : Egea J , Buendia I , Parada E , Navarro E , Leon R , Lopez MG
Ref : Biochemical Pharmacology , 97 :463 , 2015
Abstract : Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system, being expressed in neurons and non-neuronal cells, where they participate in a variety of physiological responses like memory, learning, locomotion, attention, among others. We will focus on the alpha7 nAChR subtype, which has been implicated in neuroprotection, synaptic plasticity and neuronal survival, and is considered as a potential therapeutic target for several neurological diseases. Oxidative stress and neuroinflammation are currently considered as two of the most important pathological mechanisms common in neurodegenerative diseases such as Alzheimer, Parkinson or Huntington diseases. In this review, we will first analysed the distribution and expression of nAChR in mammalian brain. Then, we focused on the function of the alpha7 nAChR subtype in neuronal and non-neuronal cells and its role in immune responses (cholinergic anti-inflammatory pathway). Finally, we will revise the anti-inflammatory pathway promoted via alpha7 nAChR activation that is related to recruitment and activation of Jak2/STAT3 pathway, which on the one hand inhibits NF-kappaB nuclear translocation, and on the other hand, activates the master regulator of oxidative stress Nrf2/HO-1. This review provides a profound insight into the role of the alpha7 nAChR subtype in microglia and point out to microglial alpha7/HO-1 pathway as an anti-inflammatory therapeutic target.
ESTHER : Egea_2015_Biochem.Pharmacol_97(4)_463
PubMedSearch : Egea_2015_Biochem.Pharmacol_97(4)_463
PubMedID: 26232730

Title : Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction - Navarro_2015_Biochem.Pharmacol_97(4)_473
Author(s) : Navarro E , Buendia I , Parada E , Leon R , Jansen-Duerr P , Pircher H , Egea J , Lopez MG
Ref : Biochemical Pharmacology , 97 :473 , 2015
Abstract : Subchronic oxidative stress and inflammation are being increasingly implicated in the pathogenesis of numerous diseases, such as Alzheimer's or Parkinson's disease. This study was designed to evaluate the potential protective role of alpha7 nicotinic receptor activation in an in vitro model of neurodegeneration based on subchronic oxidative stress. Rat organotypic hippocampal cultures (OHCs) were exposed for 4 days to low concentration of lipopolysaccharide (LPS) and the complex III mitochondrial blocker, antimycin-A. Antimycin-A (0.1muM) and lipopolysaccharide (1ng/ml) caused low neurotoxicity on their own, measured as propidium iodide fluorescence in CA1 and CA3 regions. However, their combination (LPS/AA) caused a greater detrimental effect, in addition to mitochondrial depolarization, overproduction of reactive oxygen species (ROS) and Nox4 overexpression. Antimycin-A per se increased ROS and mitochondrial depolarization, although these effects were significantly higher when combined with LPS. More interesting was the finding that exposure of OHCs to the combination of LPS/AA triggered aberrant protein aggregation, measured as thioflavin S immunofluorescence. The alpha7 nicotinic receptor agonist, PNU282987, prevented the neurotoxicity and the pathological hallmarks observed in the LPS/AA subchronic toxicity model (oxidative stress and protein aggregates); these effects were blocked by alpha-bungarotoxin and tin protoporphyrin, indicating the participation of alpha7 nAChRs and heme-oxygenase I induction. In conclusion, subchronic exposure of OHCs to low concentration of antimycin-A plus LPS reproduced pathological features of neurodegenerative disorders. alpha7 nAChR activation ameliorated these alterations by a mechanism involving heme-oxygenase I induction.
ESTHER : Navarro_2015_Biochem.Pharmacol_97(4)_473
PubMedSearch : Navarro_2015_Biochem.Pharmacol_97(4)_473
PubMedID: 26212551

Title : Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues - Martins_2011_Eur.J.Med.Chem_46_6119
Author(s) : Martins C , Carreiras MC , Leon R , de los Rios C , Bartolini M , Andrisano V , Iriepa I , Moraleda I , Galvez E , Garcia M , Egea J , Samadi A , Chioua M , Marco-Contelles J
Ref : Eur Journal of Medicinal Chemistry , 46 :6119 , 2011
Abstract : The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedlander-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines1-11 and pyrrolotacrine13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC(50) (eqBuChE)=2.9 +/- 0.4 muM; IC(50) (hBuChE)=119 +/- 15 muM]. Conversely, pyrrolotacrines 12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC(50) (EeAChE)=0.61 +/- 0.04 muM; IC(50) (eqBuChE)=0.074 +/- 0.009 muM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Abeta-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer's disease.
ESTHER : Martins_2011_Eur.J.Med.Chem_46_6119
PubMedSearch : Martins_2011_Eur.J.Med.Chem_46_6119
PubMedID: 22000936

Title : Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity - Pereira_2011_Eur.J.Pharmacol_660_411
Author(s) : Pereira JD , Caricati-Neto A , Miranda-Ferreira R , Smaili SS , Godinho RO , de los Rios C , Leon R , Villaroya M , Samadi A , Marco-Contelles J , Jurkiewicz NH , Garcia AG , Jurkiewicz A
Ref : European Journal of Pharmacology , 660 :411 , 2011
Abstract : We have recently synthesized a new series of hybrid compounds having the moieties of tacrine, a potent inhibitor of brain and peripheral acetylcholinesterase (AChE), and nimodipine, a blocker of L-type voltage-dependent calcium channels (VDCCs). These compounds were designed to target AChE and L calcium channels in the brain, as potential therapeutic agents in Alzheimer's disease. We performed the present study to determine the main peripheral side effects of two of these compounds, ITH12117 and ITH12118. We have here shown that in rat vas deferens these compounds inhibited AChE with a potency about 1000-fold lower than that of physostigmine or tacrine. Furthermore, the hybrid compounds enhanced contractions evoked by acetylcholine, with a potency about 100-fold lower than that of physostigmine or tacrine. Additionally, contractions induced by Ca2+ on depolarized vas deferens were blocked by nimodipine with greater efficacy, compared with ITH12117 and ITH12118. Compound ITH12118 (1 muM) caused a pronounced inhibition of the tonic (but not phasic) contraction elicited by electrical field stimulation. Furthermore, the same dose of nimodipine and ITH12118 blocked by 75% cytosolic Ca2+ elevations produced by acetylcholine, noradrenaline, or ATP. As a matter of comparison, we showed that rat brain cortex AChE was inhibited by ITH12118 with a potency 10 to 20-fold higher than that for vas deferens. This study shows that ITH12118 could be a paradigmatic multitarget compound having selective brain effects with smaller peripheral side effects. This may help to orient the search of new neuroprotective compounds with potential therapeutic application in Alzheimer's disease.
ESTHER : Pereira_2011_Eur.J.Pharmacol_660_411
PubMedSearch : Pereira_2011_Eur.J.Pharmacol_660_411
PubMedID: 21497158

Title : N-acylaminophenothiazines: neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer's disease - Gonzalez-Munoz_2011_Eur.J.Med.Chem_46_2224
Author(s) : Gonzalez-Munoz GC , Arce MP , Lopez B , Perez C , Romero A , Del Barrio L , Martin-de-Saavedra MD , Egea J , Leon R , Villarroya M , Lopez MG , Garcia AG , Conde S , Rodriguez-Franco MI
Ref : Eur Journal of Medicinal Chemistry , 46 :2224 , 2011
Abstract : We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an L-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Abeta peptide.
ESTHER : Gonzalez-Munoz_2011_Eur.J.Med.Chem_46_2224
PubMedSearch : Gonzalez-Munoz_2011_Eur.J.Med.Chem_46_2224
PubMedID: 21420206

Title : Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1,8-naphthyridine derivatives - de Los Rios_2010_J.Med.Chem_53_5129
Author(s) : de los Rios C , Egea J , Marco-Contelles J , Leon R , Samadi A , Iriepa I , Moraleda I , Galvez E , Garcia AG , Lopez MG , Villarroya M , Romero A
Ref : Journal of Medicinal Chemistry , 53 :5129 , 2010
Abstract : 1,8-Naphthyridine derivatives related to 17 (ITH4012), a neuroprotective compound reported by our research group, have been synthesized. In general, they have shown better inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) than most tacrine derivatives previously synthesized in our laboratory. The compounds presented an interesting neuroprotective profile in SH-SY5Y neuroblastoma cells stressed with rotenone/oligomycin A. Moreover, compound 14 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) also caused protection in cells stressed with okadaic acid (OA) or amyloid beta 1-42 peptide (Abeta(1-42)). Interestingly, compound 14 prevented the OA-induced PP2A inhibition, one of the enzymes implicated in tau dephosphorylation. This compound also exhibited neuroprotection against neurotoxicity elicited by oxygen and glucose deprivation in hippocampal slices. Because these stressors caused neuronal damage related to physiopathological hallmarks found in the brain of Alzheimer's disease (AD) patients, we conclude that compound 14 deserves further in vivo studies in AD models to test its therapeutic potential in this disease.
ESTHER : de Los Rios_2010_J.Med.Chem_53_5129
PubMedSearch : de Los Rios_2010_J.Med.Chem_53_5129
PubMedID: 20575555

Title : New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties - Leon_2008_Bioorg.Med.Chem_16_7759
Author(s) : Leon R , de los Rios C , Marco-Contelles J , Huertas O , Barril X , Luque FJ , Lopez MG , Garcia AG , Villarroya M
Ref : Bioorganic & Medicinal Chemistry , 16 :7759 , 2008
Abstract : In this communication, we describe the synthesis and biological evaluation of tacripyrimedones 1-5, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzo[b,g][1,8]naphthy ridine-1(2H)-one. These multifunctional compounds are moderately potent and selective AChEIs, with no activity toward BuChE. Kinetic analysis and molecular modeling studies point out that the new compounds preferentially bind the peripheral anionic site of AChE. In addition, compounds 1-5 show an excellent neuroprotective profile, and a moderate blocking effect of L-type voltage-dependent calcium channels due to the mitigation of [Ca(2+)] elevation elicited by K(+) depolarization. Therefore, they represent a new family of molecules with potential therapeutic application for the treatment of Alzheimer's disease.
ESTHER : Leon_2008_Bioorg.Med.Chem_16_7759
PubMedSearch : Leon_2008_Bioorg.Med.Chem_16_7759
PubMedID: 18640842

Title : Novel multipotent tacrine-dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of Alzheimer's disease - Marco-Contelles_2006_J.Med.Chem_49_7607
Author(s) : Marco-Contelles J , Leon R , de los Rios C , Guglietta A , Terencio J , Lopez MG , Garcia AG , Villarroya M
Ref : Journal of Medicinal Chemistry , 49 :7607 , 2006
Abstract : In this work we describe the synthesis and biological evaluation of the tacrine-1,4-dihydropyridine (DHP) hybrids (3-11). These multipotent molecules are the result of the juxtaposition of an acetylcholinesterase inhibitor (AChEI) such as tacrine (1) and a 1,4-DHP such as nimodipine (2). Compounds 3-11 are very selective and potent AChEIs and show an excellent neuroprotective profile and a moderate Ca2+ channel blockade effect. Consequently, these molecules are new potential drugs for the treatment of Alzheimer's disease.
ESTHER : Marco-Contelles_2006_J.Med.Chem_49_7607
PubMedSearch : Marco-Contelles_2006_J.Med.Chem_49_7607
PubMedID: 17181144

Title : Synthesis and biological evaluation of new 4H-pyrano[2,3-b]quinoline derivatives that block acetylcholinesterase and cell calcium signals, and cause neuroprotection against calcium overload and free radicals - Marco-Contelles_2006_Eur.J.Med.Chem_41_1464
Author(s) : Marco-Contelles J , Leon R , Lopez MG , Garcia AG , Villarroya M
Ref : Eur Journal of Medicinal Chemistry , 41 :1464 , 2006
Abstract : The synthesis and biological evaluation of ethyl 5-amino-4-(3-pyridyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinoline-3-car boxylates (9-11) is described. We have found that these compounds inhibit AChE with a mild potency, mitigates the [Ca(2+)](c) triggered by high K(+), and cause neuroprotection against Ca(2+) overloading and free radical-induced neuronal death.
ESTHER : Marco-Contelles_2006_Eur.J.Med.Chem_41_1464
PubMedSearch : Marco-Contelles_2006_Eur.J.Med.Chem_41_1464
PubMedID: 17030484

Title : Synthesis, acetylcholinesterase inhibition and neuroprotective activity of new tacrine analogues - Leon_2005_Bioorg.Med.Chem_13_1167
Author(s) : Leon R , Marco-Contelles J , Garcia AG , Villarroya M
Ref : Bioorganic & Medicinal Chemistry , 13 :1167 , 2005
Abstract : The synthesis and the biological evaluation (acetylcholinesterase inhibition activity and neuroprotection) of the new tacrine analogues 2-14 is described.
ESTHER : Leon_2005_Bioorg.Med.Chem_13_1167
PubMedSearch : Leon_2005_Bioorg.Med.Chem_13_1167
PubMedID: 15670925

Title : ITH4012 (ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylat e), a novel acetylcholinesterase inhibitor with calcium promotor and neuroprotective properties - Orozco_2004_J.Pharmacol.Exp.Ther_310_987
Author(s) : Orozco C , de los Rios C , Arias E , Leon R , Garcia AG , Marco JL , Villarroya M , Lopez MG
Ref : Journal of Pharmacology & Experimental Therapeutics , 310 :987 , 2004
Abstract : Ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8] naphthyridine-3-carboxylate (ITH4012) is a novel tacrine derivative that can reduce cell death induced by various compounds with different mechanisms of action, such as thapsigargin (reticular stress), H2O2 (free radicals), and veratridine (calcium overload), in bovine chromaffin cell. Cell viability, quantified as lactic dehydrogenase release, was significantly reduced by ITH4012 at concentrations ranging from 0.01 to 3 microM. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid beta25-35-induced apoptosis, determined by flow cytometry. ITH4012 caused a slight elevation in the cytosolic concentration of Ca2+ in fura 2-loaded bovine chromaffin cells, which could be related to the induction of protein synthesis relevant for cell survival. Blockade of protein synthesis by cycloheximide or blockade of Bcl-2's active site with HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) reversed the cytoprotective action of ITH4012. Furthermore, exposure of bovine chromaffin cells for 24 or 48 h to neuroprotective concentrations of this compound enhanced, nearly 3-fold, the expression of the antiapoptotic protein Bcl-2. In conclusion, ITH4012 is a tacrine derivative that maintains acetylcholinesterase-inhibiting activity (IC50=0.8 microM) but has the additional property of acting as a calcium promotor, a property leading to neuroprotection through the induction of antiapoptotic proteins.
ESTHER : Orozco_2004_J.Pharmacol.Exp.Ther_310_987
PubMedSearch : Orozco_2004_J.Pharmacol.Exp.Ther_310_987
PubMedID: 15111641