Perez B

References (28)

Title : Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors - Codony_2022_J.Med.Chem_65_13660
Author(s) : Codony S , Entrena JM , Calvo-Tusell C , Jora B , Gonzalez-Cano R , Osuna S , Corpas R , Morisseau C , Perez B , Barniol-Xicota M , Grinan-Ferre C , Perez C , Rodriguez-Franco MI , Martinez AL , Loza MI , Pallas M , Verhelst SHL , Sanfeliu C , Feixas F , Hammock BD , Brea J , Cobos EJ , Vazquez S
Ref : Journal of Medicinal Chemistry , 65 :13660 , 2022
Abstract : The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.
ESTHER : Codony_2022_J.Med.Chem_65_13660
PubMedSearch : Codony_2022_J.Med.Chem_65_13660
PubMedID: 36222708

Title : Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease - Codony_2022_J.Med.Chem_65_4909
Author(s) : Codony S , Pont C , Grinan-Ferre C , Di Pede-Mattatelli A , Calvo-Tusell C , Feixas F , Osuna S , Jarne-Ferrer J , Naldi M , Bartolini M , Loza MI , Brea J , Perez B , Bartra C , Sanfeliu C , Juarez-Jimenez J , Morisseau C , Hammock BD , Pallas M , Vazquez S , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 65 :4909 , 2022
Abstract : With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)-TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration.
ESTHER : Codony_2022_J.Med.Chem_65_4909
PubMedSearch : Codony_2022_J.Med.Chem_65_4909
PubMedID: 35271276

Title : Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP\/PS1 Mice - Viayna_2021_J.Med.Chem_64_812
Author(s) : Viayna E , Coquelle N , Cieslikiewicz-Bouet M , Cisternas P , Oliva CA , Sanchez-Lopez E , Ettcheto M , Bartolini M , De Simone A , Ricchini M , Rendina M , Pons M , Firuzi O , Perez B , Saso L , Andrisano V , Nachon F , Brazzolotto X , Garcia ML , Camins A , Silman I , Jean L , Inestrosa NC , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 64 :812 , 2021
Abstract : The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
ESTHER : Viayna_2021_J.Med.Chem_64_812
PubMedSearch : Viayna_2021_J.Med.Chem_64_812
PubMedID: 33356266
Gene_locus related to this paper: human-ACHE

Title : From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects - Pont_2021_Eur.J.Med.Chem_225_113779
Author(s) : Pont C , Ginex T , Grinan-Ferre C , Scheiner M , Mattellone A , Martinez N , Arce EM , Soriano-Fernandez Y , Naldi M , De Simone A , Barenys M , Gomez-Catalan J , Perez B , Sabate R , Andrisano V , Loza MI , Brea J , Bartolini M , Bolognesi ML , Decker M , Pallas M , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 225 :113779 , 2021
Abstract : Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Abeta42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
ESTHER : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedSearch : Pont_2021_Eur.J.Med.Chem_225_113779
PubMedID: 34418785

Title : Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor - Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
Author(s) : Cieslikiewicz-Bouet M , Naldi M , Bartolini M , Perez B , Servent D , Jean L , Araoz R , Renard PY
Ref : Biochemical Pharmacology , :114010 , 2020
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder associated with cholinergic dysfunction, provoking memory loss and cognitive dysfunction in elderly patients. The cholinergic hypothesis provided over the years with molecular targets for developing palliative treatments for AD, acting on the cholinergic system, namely, acetylcholinesterase and alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). In our synthetic work, we used "click-chemistry" to synthesize two Multi Target Directed Ligands (MTDLs) MB105 and MB118 carrying tacrine and quinuclidine scaffolds which are known for their anticholinesterase and alpha7 nicotinic acetylcholine receptor agonist activities, respectively. Both, MB105 and MB118, inhibit human acetylcholinesterase and human butyrylcholinesterase in the nanomolar range. Electrophysiological recordings on Xenopus laevis oocytes expressing human alpha7 nAChR showed that MB105 and MB118 acted as partial agonists of the referred nicotinic receptor, albeit, with different potencies despite their similar structure. The different substitution at C-3 on the 2,3-disubtituted quinuclidine scaffold may account for the significantly lower potency of MB118 compared to MB105. Electrophysiological recordings showed that the tacrine precursor MB320 behaved as a competitive antagonist of human alpha7 nAChR, in the micromolar range, while the quinuclidine synthetic precursor MB099 acted as a partial agonist. Taken all together, MB105 behaved as a partial agonist of alpha7 nAChR at concentrations where it completely inhibited human acetylcholinesterase activity paving the way for the design of novel MTDLs for palliative treatment of AD.
ESTHER : Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
PubMedSearch : Cieslikiewicz-Bouet_2020_Biochem.Pharmacol__114010
PubMedID: 32360492

Title : 2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis - Codony_2020_J.Med.Chem_63_9237
Author(s) : Codony S , Pujol E , Pizarro J , Feixas F , Valverde E , Loza MI , Brea JM , Saez E , Oyarzabal J , Pineda-Lucena A , Perez B , Perez C , Rodriguez-Franco MI , Leiva R , Osuna S , Morisseau C , Hammock BD , Vazquez-Carrera M , Vazquez S
Ref : Journal of Medicinal Chemistry , 63 :9237 , 2020
Abstract : In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.
ESTHER : Codony_2020_J.Med.Chem_63_9237
PubMedSearch : Codony_2020_J.Med.Chem_63_9237
PubMedID: 32787085

Title : Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6 - Perez-Areales_2020_J.Med.Chem_63_9360
Author(s) : Perez-Areales FJ , Garrido M , Aso E , Bartolini M , De Simone A , Espargaro A , Ginex T , Sabate R , Perez B , Andrisano V , Puigoriol-Illamola D , Pallas M , Luque FJ , Loza MI , Brea J , Ferrer I , Ciruela F , Messeguer A , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 63 :9360 , 2020
Abstract : Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, beta-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Abeta42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.
ESTHER : Perez-Areales_2020_J.Med.Chem_63_9360
PubMedSearch : Perez-Areales_2020_J.Med.Chem_63_9360
PubMedID: 32706255

Title : Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease - Grinan-Ferre_2020_Neurotherapeutics__
Author(s) : Grinan-Ferre C , Codony S , Pujol E , Yang J , Leiva R , Escolano C , Puigoriol-Illamola D , Companys-Alemany J , Corpas R , Sanfeliu C , Perez B , Loza MI , Brea J , Morisseau C , Hammock BD , Vazquez S , Pallas M , Galdeano C
Ref : Neurotherapeutics , : , 2020
Abstract : The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.
ESTHER : Grinan-Ferre_2020_Neurotherapeutics__
PubMedSearch : Grinan-Ferre_2020_Neurotherapeutics__
PubMedID: 32488482

Title : A novel class of multitarget anti-Alzheimer benzohomoadamantanechlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors - Perez-Areales_2019_Eur.J.Med.Chem_180_613
Author(s) : Perez-Areales FJ , Turcu AL , Barniol-Xicota M , Pont C , Pivetta D , Espargaro A , Bartolini M , De Simone A , Andrisano V , Perez B , Sabate R , Sureda FX , Vazquez S , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 180 :613 , 2019
Abstract : The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89muM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
ESTHER : Perez-Areales_2019_Eur.J.Med.Chem_180_613
PubMedSearch : Perez-Areales_2019_Eur.J.Med.Chem_180_613
PubMedID: 31351393

Title : Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice - Relat_2018_Int.J.Mol.Sci_19_
Author(s) : Relat J , Come J , Perez B , Camps P , Munoz-Torrero D , Badia A , Gimenez-Llort L , Clos MV
Ref : Int J Mol Sci , 19 : , 2018
Abstract : Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Abeta aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3beta, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3beta in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia.
ESTHER : Relat_2018_Int.J.Mol.Sci_19_
PubMedSearch : Relat_2018_Int.J.Mol.Sci_19_
PubMedID: 30181440

Title : Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis - Galdeano_2018_Molecules_23_
Author(s) : Galdeano C , Coquelle N , Cieslikiewicz-Bouet M , Bartolini M , Perez B , Clos MV , Silman I , Jean L , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Molecules , 23 : , 2018
Abstract : Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.
ESTHER : Galdeano_2018_Molecules_23_
PubMedSearch : Galdeano_2018_Molecules_23_
PubMedID: 29534488
Gene_locus related to this paper: torca-ACHE

Title : Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration - Zorbaz_2018_Chemistry_24_9675
Author(s) : Zorbaz T , Braiki A , Marakovic N , Renou J , De la Mora E , Macek Hrvat N , Katalinic M , Silman I , Sussman JL , Mercey G , Gomez C , Mougeot R , Perez B , Baati R , Nachon F , Weik M , Jean L , Kovarik Z , Renard PY
Ref : Chemistry , 24 :9675 , 2018
Abstract : A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential.
ESTHER : Zorbaz_2018_Chemistry_24_9675
PubMedSearch : Zorbaz_2018_Chemistry_24_9675
PubMedID: 29672968
Gene_locus related to this paper: torca-ACHE

Title : Huprine X Attenuates The Neurotoxicity Induced by Kainic Acid, Especially Brain Inflammation - Relat_2018_Basic.Clin.Pharmacol.Toxicol_122_94
Author(s) : Relat J , Perez B , Camps P , Munoz-Torrero D , Badia A , Victoria Clos M
Ref : Basic Clin Pharmacol Toxicol , 122 :94 , 2018
Abstract : Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models in vivo and in vitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In this study, we assessed the ability of HX (0.8 mg/kg, 21 days) to prevent the damage induced by kainic acid (KA; 28 mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain. KA administration significantly modified the levels of pAkt1, Bcl2, pGSK3beta, p25/p35, increased the glial cell markers and reduced the neurogenesis process. We also observed that pre-treatment with HX significantly reduced the p25/p35 ratio and increased synaptophysin levels, which suggests a protective effect against apoptosis and an improvement of neuroplasticity. The increase in GFAP (88%) and Iba-1 (72%) induced by KA was totally prevented by HX pre-treatment, underlying a relevant anti-inflammatory action of the anticholinesterasic drug. Our findings highlight the potential of HX, in particular, and of AChEIs, in general, to treat a number of diseases that course with both cognitive deficits and chronic inflammatory processes.
ESTHER : Relat_2018_Basic.Clin.Pharmacol.Toxicol_122_94
PubMedSearch : Relat_2018_Basic.Clin.Pharmacol.Toxicol_122_94
PubMedID: 28724203

Title : Behavioural effects of novel multitarget anticholinesterasic derivatives in Alzheimer's disease - Gimenez-Llort_2017_Behav.Pharmacol_28_124
Author(s) : Gimenez-Llort L , Ratia M , Perez B , Camps P , Munoz-Torrero D , Badia A , Clos MV
Ref : Behav Pharmacol , 28 :124 , 2017
Abstract : The current pharmacological approach to Alzheimer's disease (AD) treatment, mostly based on acetylcholinesterase inhibitors (AChEIs), is being revisited, especially in terms of the temporal frames and the potential benefits of their noncanonic actions, raising the question of whether inhibitors of AChE might also act in a disease-modifying manner. Besides, in the last decades, the pharmacophoric moieties of known AChEIs have been covalently linked to other pharmacophores in the pursuit of multitarget hybrid molecules that are expected to induce long-lasting amelioration of impaired neurotransmission and clinical symptoms but also to exert disease-modifying effects. Our research consortium has synthesized and defined the pharmacological profile of new AChEIs derivatives of potential interest for the treatment of AD. Among these, huprines and derivatives have been characterized successfully. Huprine X, a reversible AChE inhibitor, designed by molecular hybridization of tacrine and huperzine A, has been shown to affect the amyloidogenic process in vitro, and the AD-related neuropathology in vivo in mice models of the disease. More recently, we have shown that a group of donepezil-huprine heterodimers exerts a highly potent and selective inhibitory action on AChE both in vitro and ex vivo, simultaneously interacting with both peripheral and catalytic binding sites, and inhibiting the beta-amyloid aggregation, whereas some levetiracetam-huprine hybrids have been shown to reduce epileptiform activity, neuroinflammation and amyloid burden in an animal model of AD. Here, we summarize the behavioural correlates of these noncanonic actions as assessed in three distinct biological scenarios: middle-age, cognitive deficits associated with ageing and AD-like phenotype in mice. Besides the improvement in the hallmark cognitive symptomatology without inducing side effects, these drugs have shown to be able to modulate emotional and anxiety-like behaviours or to reduce spontaneous seizures, all of them related to the so-called 'behavioural and psychological symptoms of dementia'. Overall, the studies show that these novel multitarget anticholinesterasics exert noncanonic actions providing symptomatic and disease-modifying benefits of potential interest for the management of AD.
ESTHER : Gimenez-Llort_2017_Behav.Pharmacol_28_124
PubMedSearch : Gimenez-Llort_2017_Behav.Pharmacol_28_124
PubMedID: 28125507

Title : Design, synthesis and multitarget biological profiling of second-generation anti-Alzheimer rhein-huprine hybrids - Perez-Areales_2017_Future.Med.Chem_9_965
Author(s) : Perez-Areales FJ , Betari N , Viayna A , Pont C , Espargaro A , Bartolini M , De Simone A , Rinaldi Alvarenga JF , Perez B , Sabate R , Lamuela-Raventos RM , Andrisano V , Luque FJ , Munoz-Torrero D
Ref : Future Med Chem , 9 :965 , 2017
Abstract : AIM: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. MATERIALS &
METHODS: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Abeta42 and tau aggregation, of antioxidant activity, and of brain permeation.
RESULTS: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Abeta42 and tau antiaggregating and antioxidant activities. CONCLUSION: Second-generation naphthyridine- and thienopyridine-based rhein-huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.
ESTHER : Perez-Areales_2017_Future.Med.Chem_9_965
PubMedSearch : Perez-Areales_2017_Future.Med.Chem_9_965
PubMedID: 28632395

Title : Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity - Di Pietro_2015_Eur.J.Med.Chem_105_120
Author(s) : Di Pietro O , Vicente-Garcia E , Taylor MC , Berenguer D , Viayna E , Lanzoni A , Sola I , Sayago H , Riera C , Fisa R , Clos MV , Perez B , Kelly JM , Lavilla R , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 105 :120 , 2015
Abstract : Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 muM, 6.1 muM and 29.2 muM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 muM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
ESTHER : Di Pietro_2015_Eur.J.Med.Chem_105_120
PubMedSearch : Di Pietro_2015_Eur.J.Med.Chem_105_120
PubMedID: 26479031

Title : Dodecenyl succinylated alginate as a novel material for encapsulation and hyperactivation of lipases - Falkeborg_2015_Carbohydr.Polym_133_194
Author(s) : Falkeborg M , Paitaid P , Shu AN , Perez B , Guo Z
Ref : Carbohydr Polym , 133 :194 , 2015
Abstract : Alginate was modified with dodecenyl succinic anhydride (SAC12) in an aqueous reaction medium at neutral pH. The highest degree of succinylation (33.9+/-3.5%) was obtained after 4h at 30 degrees C, using four mole SAC12 per mol alginate monomer. Alginate was modified with succinic anhydride (SAC0) for comparison, and the structures and thermal properties of alg-SAC0 and alg-SAC12 were evaluated using FTIR, (1)H NMR, and DSC. Calcium-hydrogel beads were formed from native and modified alginates, in which lipases were encapsulated with a load of averagely 76mug lipase per mg alginate, irrespective of the type of alginate. Lipases with a "lid", which usually are dependent on interfacial activation, showed a 3-fold increase in specific activity toward water-soluble substrates when encapsulated in alg-SAC12, compared to the free lipase. Such hyperactivation was not observed for lipases independent of interfacial activation, or for lipases encapsulated in native alginate or alg-SAC0 hydrogels.
ESTHER : Falkeborg_2015_Carbohydr.Polym_133_194
PubMedSearch : Falkeborg_2015_Carbohydr.Polym_133_194
PubMedID: 26344272

Title : AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: Studies in cognitively poor middle-aged mice - Gimenez-Llort_2015_Behav.Brain.Res_286_97
Author(s) : Gimenez-Llort L , Ratia M , Perez B , Camps P , Munoz-Torrero D , Badia A , Clos MV
Ref : Behavioural Brain Research , 286 :97 , 2015
Abstract : The present work describes, for the first time, the in vivo effects of the multitarget compound AVCRI104P3, a new anticholinesterasic drug with potent inhibitory effects on human AChE, human BCHE and BACE-1 activities as well as on the AChE-induced and self-induced Abeta aggregation. We characterized the behavioral effects of chronic treatment with AVCRI104P3 (0.6mumolkg-1, i.p., 21 days) in a sample of middle aged (12-month-old) male 129/SvxC57BL/6 mice with poor cognitive performance, as shown by the slow acquisition curves of saline-treated animals. Besides, a comparative assessment of cognitive and non-cognitive actions was done using its in vitro equipotent doses of huprine X (0.12mumolkg-1), a huperzine A-tacrine hybrid. The screening assessed locomotor activity, anxiety-like behaviors, cognitive function and side effects. The results on the 'acquisition' of spatial learning and memory show that AVCRI104P3 exerted pro-cognitive effects improving both short- and long-term processes, resulting in a fast and efficient acquisition of the place task in the Morris water maze. On the other hand, a removal test and a perceptual visual learning task indicated that both AChEIs improved short-term 'memory' as compared to saline treated mice. Both drugs elicited the same response in the corner test, but only AVCRI104P3 exhibited anxiolytic-like actions in the dark/light box test. These cognitive-enhancement and anxiolytic-like effects demostrated herein using a sample of middle-aged animals and the lack of adverse effects, strongly encourage further studies on AVCRI104P3 as a promising multitarget therapeutic agent for the treatment of cholinergic dysfunction underlying natural aging and/or dementias.
ESTHER : Gimenez-Llort_2015_Behav.Brain.Res_286_97
PubMedSearch : Gimenez-Llort_2015_Behav.Brain.Res_286_97
PubMedID: 25732954

Title : Characterization and mechanism insight of accelerated catalytic promiscuity of Sulfolobus tokodaii (ST0779) peptidase for aldol addition reaction - Li_2015_Appl.Microbiol.Biotechnol_99_9625
Author(s) : Li R , Perez B , Jian H , Jensen MM , Gao R , Dong M , Glasius M , Guo Z
Ref : Applied Microbiology & Biotechnology , 99 :9625 , 2015
Abstract : A novel peptidase from thermophilic archaea Sulfolobus tokodaii (ST0779) is examined for its catalytic promiscuity of aldol addition, which shows comparable activity as porcine pancreatic lipase (PPL, one of the best enzymes identified for biocatalytic aldol addition) at 30 degrees C but much accelerated activity at elevated temperature. The molecular catalytic efficiency kcat/Km (M(-1) s(-1)) of this thermostable enzyme at 55 degrees C adds up to 140 times higher than that of PPL at its optimum temperature 37 degrees C. The fluorescence quenching analysis depicts that the binding constants of PPL are significantly higher than those of ST0779, and their numbers of binding sites show opposite temperature dependency. Thermodynamic parameters estimated by fluorescence quenching analysis unveil distinctly different substrate-binding modes between PPL and ST0779: the governing binding interaction between PPL and substrates is hydrophobic force, while the dominating substrate-binding forces for ST0779 are van der Waals and H-bonds interactions. A reasonable mechanism for ST0779-catalyzed aldol reaction is proposed based on kinetic study, spectroscopic analysis, and molecular stereostructure simulation. This work represents a successful example to identify a new enzyme for catalytic promiscuity, which demonstrates a huge potential to discover and exploit novel biocatalyst from thermophile microorganism sources.
ESTHER : Li_2015_Appl.Microbiol.Biotechnol_99_9625
PubMedSearch : Li_2015_Appl.Microbiol.Biotechnol_99_9625
PubMedID: 26169629
Gene_locus related to this paper: sulto-ST0779

Title : Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity - Sola_2015_Bioorg.Med.Chem_23_5156
Author(s) : Sola I , Castella S , Viayna E , Galdeano C , Taylor MC , Gbedema SY , Perez B , Clos MV , Jones DC , Fairlamb AH , Wright CW , Kelly JM , Munoz-Torrero D
Ref : Bioorganic & Medicinal Chemistry , 23 :5156 , 2015
Abstract : Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
ESTHER : Sola_2015_Bioorg.Med.Chem_23_5156
PubMedSearch : Sola_2015_Bioorg.Med.Chem_23_5156
PubMedID: 25678015

Title : Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines - Sola_2014_Bioorg.Med.Chem.Lett_24_5435
Author(s) : Sola I , Artigas A , Taylor MC , Gbedema SY , Perez B , Clos MV , Wright CW , Kelly JM , Munoz-Torrero D
Ref : Bioorganic & Medicinal Chemistry Lett , 24 :5435 , 2014
Abstract : We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio.
ESTHER : Sola_2014_Bioorg.Med.Chem.Lett_24_5435
PubMedSearch : Sola_2014_Bioorg.Med.Chem.Lett_24_5435
PubMedID: 25454267

Title : Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties - Perez-Areales_2014_Bioorg.Med.Chem_22_5298
Author(s) : Perez-Areales FJ , Di Pietro O , Espargaro A , Vallverdu-Queralt A , Galdeano C , Ragusa IM , Viayna E , Guillou C , Clos MV , Perez B , Sabate R , Lamuela-Raventos RM , Luque FJ , Munoz-Torrero D
Ref : Bioorganic & Medicinal Chemistry , 22 :5298 , 2014
Abstract : Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS(+), DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Abeta42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Abeta42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.
ESTHER : Perez-Areales_2014_Bioorg.Med.Chem_22_5298
PubMedSearch : Perez-Areales_2014_Bioorg.Med.Chem_22_5298
PubMedID: 25156301

Title : Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents - Viayna_2014_J.Med.Chem_57_2549
Author(s) : Viayna E , Sola I , Bartolini M , De Simone A , Tapia-Rojas C , Serrano FG , Sabate R , Juarez-Jimenez J , Perez B , Luque FJ , Andrisano V , Clos MV , Inestrosa NC , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 57 :2549 , 2014
Abstract : We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Abeta42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Abeta-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Abeta lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.
ESTHER : Viayna_2014_J.Med.Chem_57_2549
PubMedSearch : Viayna_2014_J.Med.Chem_57_2549
PubMedID: 24568372

Title : Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies - Di Pietro_2014_Eur.J.Med.Chem_84C_107
Author(s) : Di Pietro O , Perez-Areales FJ , Juarez-Jimenez J , Espargaro A , Clos MV , Perez B , Lavilla R , Sabate R , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 84C :107 , 2014
Abstract : Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O --> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Abeta42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.
ESTHER : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedSearch : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedID: 25016233

Title : 1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies - Di Pietro_2013_Eur.J.Med.Chem_73C_141
Author(s) : Di Pietro O , Viayna E , Vicente-Garcia E , Bartolini M , Ramon R , Juarez-Jimenez J , Clos MV , Perez B , Andrisano V , Luque FJ , Lavilla R , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 73C :141 , 2013
Abstract : A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O --> NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.
ESTHER : Di Pietro_2013_Eur.J.Med.Chem_73C_141
PubMedSearch : Di Pietro_2013_Eur.J.Med.Chem_73C_141
PubMedID: 24389509

Title : Undifferentiated and Differentiated PC12 Cells Protected by Huprines Against Injury Induced by Hydrogen Peroxide - Pera_2013_PLoS.One_8_e74344
Author(s) : Pera M , Camps P , Munoz-Torrero D , Perez B , Badia A , Clos Guillen MV
Ref : PLoS ONE , 8 :e74344 , 2013
Abstract : Oxidative stress is implicated in the pathogenesis of neurodegenerative disorders and hydrogen peroxide (H2O2) plays a central role in the stress. Huprines, a group of potent acetylcholinesterase inhibitors (AChEIs), have shown a broad cholinergic pharmacological profile. Recently, it has been observed that huprine X (HX) improves cognition in non transgenic middle aged mice and shows a neuroprotective activity (increased synaptophysin expression) in 3xTg-AD mice. Consequently, in the present experiments the potential neuroprotective effect of huprines (HX, HY, HZ) has been analyzed in two different in vitro conditions: undifferentiated and NGF-differentiated PC12 cells. Cells were subjected to oxidative insult (H2O2, 200 microM) and the protective effects of HX, HY and HZ (0.01 microM-1 microM) were analyzed after a pre-incubation period of 24 and 48 hours. All huprines showed protective effects in both undifferentiated and NGF-differentiated cells, however only in differentiated cells the effect was dependent on cholinergic receptors as atropine (muscarinic antagonist, 0.1 microM) and mecamylamine (nicotinic antagonist, 100 microM) reverted the neuroprotection action of huprines. The decrease in SOD activity observed after oxidative insult was overcome in the presence of huprines and this effect was not mediated by muscarinic or nicotinic receptors. In conclusion, huprines displayed neuroprotective properties as previously observed in in vivo studies. In addition, these effects were mediated by cholinergic receptors only in differentiated cells. However, a non-cholinergic mechanism, probably through an increase in SOD activity, seems to be also involved in the neuroprotective effects of huprines.
ESTHER : Pera_2013_PLoS.One_8_e74344
PubMedSearch : Pera_2013_PLoS.One_8_e74344
PubMedID: 24086337

Title : Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer's Disease in Triple Transgenic Mice (3xTg-AD) - Ratia_2013_Neurodegener.Dis_11_129
Author(s) : Ratia M , Gimenez-Llort L , Camps P , Munoz-Torrero D , Perez B , Clos MV , Badia A
Ref : Neurodegener Dis , 11 :129 , 2013
Abstract : Background: Different studies have established that cholinergic neurodegeneration could be a major pathological feature of Alzheimer's disease (AD). Thus, enhancement of the central cholinergic neurotransmission has been regarded as one of the most promising strategies for the symptomatic treatment of AD, mainly by means of reversible acetylcholinesterase inhibitors (AChEIs). The cognitive-enhancing properties of both huprine X, a new AChEI, and the structurally related huperzine A, as well as their effects on the regulation of several neurochemical processes related to AD have been studied in triple transgenic mice (3xTg-AD). Methods: Seven-month-old homozygous 3xTg-AD male mice, which received chronic intraperitoneal treatment with either saline, huprine X (0.12 or huperzine A (0.8 were subjected to a battery of behavioural tests after 3 weeks of treatment and thereafter the brains were dissected to study the neurochemical effects induced by the two AChEIs. Results: Treatments with huprine X and huperzine A improved learning and memory in the Morris water maze and some indicators of emotionality without inducing important adverse effects. Moreover, huprine X and huperzine A activate protein kinase C/mitogen-activated protein kinase pathway signalling, alpha-secretases (ADAM 10 and TACE) and increase the fraction of phospho-glycogen synthase kinase 3-beta. Conclusion: Results obtained herein using a sample of 3xTg-AD animals strongly suggest that the treatment with the two AChEIs not only improves the cognitive performance of the animals but also induces some neurochemical changes that could contribute to the beneficial effects observed.
ESTHER : Ratia_2013_Neurodegener.Dis_11_129
PubMedSearch : Ratia_2013_Neurodegener.Dis_11_129
PubMedID: 22626981

Title : The beta 5' loop of the pancreatic lipase C2-like domain plays a critical role in the lipase-lipid interactions - Chahinian_2002_Biochemistry_41_13725
Author(s) : Chahinian H , Bezzine S , Ferrato F , Ivanova MG , Perez B , Lowe ME , Carriere F
Ref : Biochemistry , 41 :13725 , 2002
Abstract : The structural similarities between the C-terminal domain of human pancreatic lipase (C-HPL) and C2 domains suggested a similar function, the interaction with lipids. The catalytic N-terminal domain (N-HPL) and C-HPL were produced as individual proteins, and their partitioning between the water phase and the triglyceride-water interface was assessed using trioctanoin emulsions (TC8). N-HPL did not bind efficiently to TC8 and was inactive. C-HPL did bind to TC8 and to a phospholipid monolayer with a critical surface pressure of penetration similar to that of HPL (15 mN m(-1)). These experiments, performed in the absence of colipase and bile salts, support an absolute requirement of C-HPL for interfacial binding of HPL. To refine our analysis, we determined the contribution to lipid interactions of a hydrophobic loop (beta 5') in C-HPL by investigating a HPL mutant in which beta 5' loop hydrophobicity was increased by introducing the homologous lipoprotein lipase (LPL) beta 5' loop. This mutant (HPL-beta 5'LPL) penetrated into phospholipid monolayers at higher surface pressures than HPL, and its level of binding to TC8 was higher than that of HPL in the presence of serum albumin (BSA), an inhibitory protein that competes with HPL for interfacial adsorption. The beta 5' loop of LPL is therefore tailored for an optimal interaction with the surface of triglyceride-rich lipoproteins (VLDL and chylomicrons) containing phospholipids and apoproteins. These observations support a major contribution of the beta 5' loop in the interaction of LPL and HPL with their respective substrates.
ESTHER : Chahinian_2002_Biochemistry_41_13725
PubMedSearch : Chahinian_2002_Biochemistry_41_13725
PubMedID: 12427035