Badia A

References (38)

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 : 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 : 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 : 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 micromol.kg(-1)) or huperzine A (0.8 micromol.kg(-1)) 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 : Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases - Galdeano_2012_J.Med.Chem_55_661
Author(s) : Galdeano C , Viayna E , Sola I , Formosa X , Camps P , Badia A , Clos MV , Relat J , Ratia M , Bartolini M , Mancini F , Andrisano V , Salmona M , Minguillon C , Gonzalez-Munoz GC , Rodriguez-Franco MI , Bidon-Chanal A , Luque FJ , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 55 :661 , 2012
Abstract : A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.
ESTHER : Galdeano_2012_J.Med.Chem_55_661
PubMedSearch : Galdeano_2012_J.Med.Chem_55_661
PubMedID: 22185619

Title : Expanding the multipotent profile of huprine-tacrine heterodimers as disease-modifying anti-Alzheimer agents - Munoz-Torrero_2012_Neurodegener.Dis_10_96
Author(s) : Munoz-Torrero D , Pera M , Relat J , Ratia M , Galdeano C , Viayna E , Sola I , Formosa X , Camps P , Badia A , Clos MV
Ref : Neurodegener Dis , 10 :96 , 2012
Abstract : BACKGROUND: Multifactorial diseases such as Alzheimer's disease (AD) should be more efficiently tackled by drugs which hit multiple biological targets involved in their pathogenesis. We have recently developed a new family of huprine-tacrine heterodimers, rationally designed to hit multiple targets involved upstream and downstream in the neurotoxic cascade of AD, namely beta-amyloid aggregation and formation as well as acetylcholinesterase catalytic activity. OBJECTIVE: In this study, the aim was to expand the pharmacological profiling of huprine-tacrine heterodimers investigating their effect on muscarinic M(1) receptors as well as their neuroprotective effects against an oxidative insult. METHODS: Sprague-Dawley rat hippocampus homogenates were used to assess the specific binding of two selected compounds in competition with 1 nM [(3)H]pirenzepine (for M(1) receptors) or 0.8 nM [(3)H]quinuclidinyl benzilate (for M(2) receptors). For neuroprotection studies, SHSY5Y cell cultures were subjected to 250 muM hydrogen peroxide insult with or without preincubation with some huprine-tacrine heterodimers. RESULTS: A low nanomolar affinity and M(1)/M(2) selectivity has been found for the selected compounds. Huprine-tacrine heterodimers are not neurotoxic to SHSY5Y cells at a range of concentrations from 1 to 0.001 muM, and some of them can protect cells from the oxidative damage produced by hydrogen peroxide at concentrations as low as 0.001 muM. CONCLUSION: Even though it remains to be determined if these compounds act as agonists at M(1) receptors, as it is the case of the parent huprine Y, their low nanomolar M(1) affinity and neuroprotective effects expand their multitarget profile and increase their interest as disease-modifying anti-Alzheimer agents.
ESTHER : Munoz-Torrero_2012_Neurodegener.Dis_10_96
PubMedSearch : Munoz-Torrero_2012_Neurodegener.Dis_10_96
PubMedID: 22236498

Title : Novel huprine derivatives with inhibitory activity toward beta-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates - Viayna_2010_ChemMedChem_5_1855
Author(s) : Viayna E , Gomez T , Galdeano C , Ramirez L , Ratia M , Badia A , Clos MV , Verdaguer E , Junyent F , Camins A , Pallas M , Bartolini M , Mancini F , Andrisano V , Arce MP , Rodriguez-Franco MI , Bidon-Chanal A , Luque FJ , Camps P , Munoz-Torrero D
Ref : ChemMedChem , 5 :1855 , 2010
Abstract : A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced beta-amyloid (Abeta) aggregation and beta-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Abeta aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.
ESTHER : Viayna_2010_ChemMedChem_5_1855
PubMedSearch : Viayna_2010_ChemMedChem_5_1855
PubMedID: 20859987

Title : Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates - Camps_2010_Chem.Biol.Interact_187_411
Author(s) : Camps P , Formosa X , Galdeano C , Gomez T , Munoz-Torrero D , Ramirez L , Viayna E , Gomez E , Isambert N , Lavilla R , Badia A , Clos MV , Bartolini M , Mancini F , Andrisano V , Bidon-Chanal A , Huertas O , Dafni T , Luque FJ
Ref : Chemico-Biological Interactions , 187 :411 , 2010
Abstract : Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.
ESTHER : Camps_2010_Chem.Biol.Interact_187_411
PubMedSearch : Camps_2010_Chem.Biol.Interact_187_411
PubMedID: 20167211

Title : Effect of huprine X on beta-amyloid, synaptophysin and alpha7 neuronal nicotinic acetylcholine receptors in the brain of 3xTg-AD and APPswe transgenic mice - Hedberg_2010_Neurodegener.Dis_7_379
Author(s) : Hedberg MM , Clos MV , Ratia M , Gonzalez D , Lithner CU , Camps P , Munoz-Torrero D , Badia A , Gimenez-Llort L , Nordberg A
Ref : Neurodegener Dis , 7 :379 , 2010
Abstract : BACKGROUND: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer's disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivo in two mouse models. METHODS: Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 mumol/kg, i.p., 21 days) or saline at 6-7 months. Human beta-amyloid (Abeta) was measured by ELISA, synaptophysin by Western blot and alpha7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [(125)I]alpha-bungarotoxin autoradiography. RESULTS: Treatment with HX reduced insoluble Abeta1-40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of alpha7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal alpha7 nAChRs in APPswe mice. CONCLUSION: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Abeta and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.
ESTHER : Hedberg_2010_Neurodegener.Dis_7_379
PubMedSearch : Hedberg_2010_Neurodegener.Dis_7_379
PubMedID: 20689242

Title : Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds - Camps_2009_J.Med.Chem_52_5365
Author(s) : Camps P , Formosa X , Galdeano C , Munoz-Torrero D , Ramirez L , Gomez E , Isambert N , Lavilla R , Badia A , Clos MV , Bartolini M , Mancini F , Andrisano V , Arce MP , Rodriguez-Franco MI , Huertas O , Dafni T , Luque FJ
Ref : Journal of Medicinal Chemistry , 52 :5365 , 2009
Abstract : Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.
ESTHER : Camps_2009_J.Med.Chem_52_5365
PubMedSearch : Camps_2009_J.Med.Chem_52_5365
PubMedID: 19663388

Title : Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process - Pera_2009_Mol.Cell.Neurosci_40_217
Author(s) : Pera M , Martinez-Otero A , Colombo L , Salmona M , Ruiz-Molina D , Badia A , Clos MV
Ref : Molecular & Cellular Neurosciences , 40 :217 , 2009
Abstract : Acetylcholinesterase (AChE) triggers beta amyloid plaques formation and is associated with amyloid plaques in the brain. Recent studies have demonstrated that AChE promotes the aggregation of PrP106-126, a peptide deduced from the prion protein sequence. In the present study we show that AChE triggers also the fibrillization of the main component of the amyloid plaques -the peptide spanning residues 82-146 (PrP82-146)- found in patients with Gerstmann-Straussler-Scheinker disease (GSS). The kinetics of PrP82-146 aggregate formation was directly correlated with AChE concentration and mature fibrils showed the tinctorial and optical properties of amyloid. Atomic force microscopy analysis showed that oligomer and amyloid fibril formation were significantly accelerated by AChE. This effect was mediated by the peripheral site of the enzyme since propidium iodide inhibited the fibrillization process. Present results strongly support the role of AChE in triggering amyloidogenesis and the potential therapeutic relevance of peripheral site blocker compounds.
ESTHER : Pera_2009_Mol.Cell.Neurosci_40_217
PubMedSearch : Pera_2009_Mol.Cell.Neurosci_40_217
PubMedID: 19038345

Title : Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation - Camps_2008_J.Med.Chem_51_3588
Author(s) : Camps P , Formosa X , Galdeano C , Gomez T , Munoz-Torrero D , Scarpellini M , Viayna E , Badia A , Clos MV , Camins A , Pallas M , Bartolini M , Mancini F , Andrisano V , Estelrich J , Lizondo M , Bidon-Chanal A , Luque FJ
Ref : Journal of Medicinal Chemistry , 51 :3588 , 2008
Abstract : A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.
ESTHER : Camps_2008_J.Med.Chem_51_3588
PubMedSearch : Camps_2008_J.Med.Chem_51_3588
PubMedID: 18517184

Title : Acetylcholinesterase triggers the aggregation of PrP 106-126 - Pera_2006_Biochem.Biophys.Res.Commun_346_89
Author(s) : Pera M , Roman S , Ratia M , Camps P , Munoz-Torrero D , Colombo L , Manzoni C , Salmona M , Badia A , Clos MV
Ref : Biochemical & Biophysical Research Communications , 346 :89 , 2006
Abstract : Acetylcholinesterase (AChE), a senile plaque component, promotes amyloid-beta-protein (Abeta) fibril formation in vitro. The presence of prion protein (PrP) in Alzheimer's disease (AD) senile plaques prompted us to assess if AChE could trigger the PrP peptides aggregation as well. Consequently, the efficacy of AChE on the PrP peptide spanning-residues 106-126 aggregation containing a coumarin fluorescence probe (coumarin-PrP 106-126) was studied. Kinetics of coumarin-PrP 106-126 aggregation showed a significant increase of maximum size of aggregates (MSA), which was dependent on AChE concentration. AChE-PrP 106-126 aggregates showed the tinctorial and optical amyloid properties as determined by polarized light and electronic microscopy analysis. A remarkable inhibition of MSA was obtained with propidium iodide, suggesting that AChE triggers PrP 106-126 and Abeta aggregation through a similar mechanism. Huprines (AChE inhibitors) also significantly decreased MSA induced by AChE as well, unveiling the potential interest for some AChE inhibitors as a novel class of potential anti-prion drugs.
ESTHER : Pera_2006_Biochem.Biophys.Res.Commun_346_89
PubMedSearch : Pera_2006_Biochem.Biophys.Res.Commun_346_89
PubMedID: 16750169

Title : Binding of 13-amidohuprines to acetylcholinesterase: exploring the ligand-induced conformational change of the gly117-gly118 peptide bond in the oxyanion hole - Camps_2006_J.Med.Chem_49_6833
Author(s) : Camps P , Gomez E , Munoz-Torrero D , Badia A , Clos MV , Curutchet C , Munoz-Muriedas J , Luque FJ
Ref : Journal of Medicinal Chemistry , 49 :6833 , 2006
Abstract : The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designed to enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (-)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives are more potent human AChE inhibitors than tacrine and (-)-huperzine A, none of them equals the potency of huprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118 conformational flip induced upon binding of (-)-huperzine A, leading to a similar pattern of interactions as that formed by the pyridone amido group of (-)-huperzine A. The detrimental effect on the binding affinity relative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with the ligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensure the preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residues Gly117 and Gly118 play a relevant role in mediating substrate recognition.
ESTHER : Camps_2006_J.Med.Chem_49_6833
PubMedSearch : Camps_2006_J.Med.Chem_49_6833
PubMedID: 17154513

Title : Effect of acetylcholinesterase inhibitors on AChE-induced PrP106-126 aggregation - Clos_2006_J.Mol.Neurosci_30_89
Author(s) : Clos MV , Pera M , Ratia M , Roman S , Camps P , Munoz-Torrero D , Colombo L , Salmona M , Badia A
Ref : Journal of Molecular Neuroscience , 30 :89 , 2006
Abstract : Transmissible spongiform encephalopaties are caused by an extracellular surface protein, the scrapie prion protein (PrPsc), which is an aberrant form of normal and functional cellular PrP (PrPc). The pathological hallmarks of these diseases are the accumulation and deposition of PrPsc in the form of amyloid fibrils in the central nervous system (Tateishi et al., 1988), similar to amyloid-beta (Abeta) protein in Alzheimer's disease (AD). In some patients, Abeta and prion pathology can coexist (Hainfellner et al., 1998), and a common spatial pattern of protein deposition has been described (Armstrong et al., 2001). In addition, it is well-known that acetylcholinesterase (AChE) colocalizes with Abeta deposits of brains in AD patients and accelerates assembly of Abeta peptides through the peripheral site of the enzyme (Inestrosa et al., 1996). The aim of the present study was to analyze time course and concentration dependence of the AChE proaggregating effect on synthetic peptide-spanning residues 106-126 of human PrP (PrP106-126) and the reversion of this effect by different AChE inhibitors (AChEIs).
ESTHER : Clos_2006_J.Mol.Neurosci_30_89
PubMedSearch : Clos_2006_J.Mol.Neurosci_30_89
PubMedID: 17192641

Title : Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors - Camps_2005_J.Med.Chem_48_1701
Author(s) : Camps P , Formosa X , Munoz-Torrero D , Petrignet J , Badia A , Clos MV
Ref : Journal of Medicinal Chemistry , 48 :1701 , 2005
Abstract : A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC(50) values in the subnanomolar and low nanomolar range, respectively.
ESTHER : Camps_2005_J.Med.Chem_48_1701
PubMedSearch : Camps_2005_J.Med.Chem_48_1701
PubMedID: 15771413

Title : Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors - Roman_2005_Brain.Res_1061_73
Author(s) : Roman S , Badia A , Camps P , Munoz-Torrero D , Clos MV
Ref : Brain Research , 1061 :73 , 2005
Abstract : The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors.
ESTHER : Roman_2005_Brain.Res_1061_73
PubMedSearch : Roman_2005_Brain.Res_1061_73
PubMedID: 16248990

Title : Potentiation effects of (+\/-)huprine X, a new acetylcholinesterase inhibitor, on nicotinic receptors in rat cortical synaptosomes - Roman_2004_Neuropharmacol_46_95
Author(s) : Roman S , Badia A , Camps P , Clos MV
Ref : Neuropharmacology , 46 :95 , 2004
Abstract : The present experiments were developed to analyze the direct and/or potentiation effect of (+/-)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quin oline hydrochloride ((+/-)huprine X) on nicotinic receptors using a synaptosomal superfusion method. (+/-)Huprine X (1 microM, 10 microM) increased [(3)H]-ACh release only at 10 microM (46%; P < 0.001) in basal, but not in stimulated, conditions. This effect was completely reverted by mecamylamine (100 microM; MEC). Potentiation of evoked-[3H]-ACh release induced by ACh (1 microM) and by galantamine (GAL) 0.4 microM and physostigmine (PHY) 10 microM (55% and 50%, respectively; P < 0.001), two well-known allosteric compounds, corroborate that the present experimental approach is a suitable method to study potentiation effects on nicotinic receptors in the central nervous system nerve terminals. (+/-)Huprine X potentiated the evoked-[3H]-ACh release induced by ACh (1 microM) by 166% and 90% (P < 0.001) at 10 microM and 30 microM, respectively, and this effect was completely blocked by MEC (100 microM). In the presence of different ACh concentrations, (+/-)huprine X 10 microM potentiated evoked-[3H]-ACh release at low ACh concentrations, while a decrease in neurotransmitter release was observed at high ACh concentrations. The highest potentiation effect was obtained at the ACh/(+/-)huprine X concentration ratio of 1:10, and this potentiation was observed at as low a (+/-)huprine X concentration as 0.1 microM (P < 0.05). While the results suggest that huprine may enhance the potency or effectiveness of ACh by an effect involving nicotinic receptors we cannot completely discard that the results could be explained by acetylcholine esterase inhibition.
ESTHER : Roman_2004_Neuropharmacol_46_95
PubMedSearch : Roman_2004_Neuropharmacol_46_95
PubMedID: 14654101

Title : Characterisation of the anticholinesterase activity of two new tacrine-huperzine A hybrids - Alcala_2003_Neuropharmacol_44_749
Author(s) : Alcala Mdel M , Vivas NM , Hospital S , Camps P , Munoz-Torrero D , Badia A
Ref : Neuropharmacology , 44 :749 , 2003
Abstract : The effects of two tacrine-huperzine A hybrids, (+/-)-huprine Y and (+/-)-huprine Z, have been evaluated. Bovine and human acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) inhibition were assayed by Ellman's method. The two huprines were more active than both tacrine and (-)-huperzine A as inhibitors of both human and bovine AChE, and they acted as mixed-type AChE inhibitors. Moreover, (+/-)-huprine Y exhibited a tight binding character seen in the experiments of reversibility of bovine AChE inhibitory activity. In addition, both compounds were more active toward AChE than toward BChE. Also, the selectivity for the human AChE was greater than for the bovine enzyme. In ex vivo studies performed in mice, both drugs showed a clear inhibitory activity of brain AChE, 20 min after i.p. injection, (+/-)-huprine Y being more potent than (+/-)-huprine Z [ID(50) 1.09 (0.39-2.98) vs. 5.77 (3.29-10.30) micromol/kg]. The time-course study of the inhibitory effect displayed a t(1/2) of 1 h for the two compounds. These results show that these drugs are two potent, central AChE inhibitors of potential interest in the treatment of AD.
ESTHER : Alcala_2003_Neuropharmacol_44_749
PubMedSearch : Alcala_2003_Neuropharmacol_44_749
PubMedID: 12681373

Title : Synthesis and Acetylcholinesterase\/Butyrylcholinesterase Inhibition Activity of 4-Amino-2, 3-diaryl-5, 6, 7, 8-tetrahydrofuro(and thieno)[2, 3-b]-quinolines, and 4-Amino-5, 6, 7, 8, 9-pentahydro-2, 3-diphenylcyclohepta[e]furo(and thieno)-[2, 3-b]pyridines - Marco_2002_Arch.Pharm.(Weinheim)_335_347
Author(s) : Marco JL , de los Rios C , Carreiras MC , Banos JE , Badia A , Vivas NM
Ref : Arch Pharm (Weinheim) , 335 :347 , 2002
Abstract : The acetylcholinesterase (AChE) and butyrylcholinesterase (BCHE) inhibition activities of a series of 4-amino-2, 3-diaryl-5, 6, 7, 8-tetrahydrofuro[2, 3-b]quinolines (10-12)/4-amino-5, 6, 7, 8-tetrahydro-2, 3-diphenylthieno[2, 3-b]quinoline (14) and 4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-diphenylcyclohepta[e]furo[2, 3-b]pyridine (13)/4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-phenylcyclohepta[e]thieno[2, 3-b]pyridine (15) are described. These compounds are tacrine (THA) analogues which have been prepared either from readily available 2-amino-3-cyano-4, 5-diarylfurans (16-18) or from 2-amino-3-cyano-4, 5-diphenylthiophene (19), via Friedlnnder condensation with cyclohexanone or cycloheptanone. These compounds are competitive inhibitors for acetylcholinesterase, the more potent being compound (13) which is three-fold less active than tacrine. The butyrylcholinesterase inhibition activity is significant only in compounds 10 and133, which are ten-fold less active than tacrine. It is found that the products 11 and 12 strongly inhibit acetylcholinesterase, and show excellent selectivity regarding butyrylcholinesterase.
ESTHER : Marco_2002_Arch.Pharm.(Weinheim)_335_347
PubMedSearch : Marco_2002_Arch.Pharm.(Weinheim)_335_347
PubMedID: 12207285

Title : Interaction of a new potent anticholinesterasic compound (+\/-)huprine X with muscarinic receptors in rat brain - Roman_2002_Neurosci.Lett_325_103
Author(s) : Roman S , Vivas NM , Badia A , Clos MV
Ref : Neuroscience Letters , 325 :103 , 2002
Abstract : The interaction of rac-12-amine-3-clor-6,7,10,11-tetrahydro-9-ethyl-7-11-methanecyclo-octane[b]quino line ((+/-)huprine X) with M(1) and M(2) receptors has been studied in rat brain. Specific binding of [(3)H]pirenzepine or [(3)H]quinuclinidylbenzylate to hippocampus preparations was inhibited by (+/-)huprine X. This drug displayed a greater affinity for M(1) (K(i)=0.338+/-0.41 microM) than M(2) (K(i)=4.66+/-0.32 microM) receptors. In functional studies, (+/-)huprine X (1 microM) increased the release of [(3)H]dopamine in cortical synaptosomes, and this effect was partially reverted by atropine and mecamylamine, suggesting an agonistic effect on both M(1) and nicotinic receptors. The inhibitory effect of (+/-)huprine X (10 microM) on [(3)H]acetylcholine release and the subsequent reversion by atropine suggests that the drug also has an agonist effect on M(2) receptors. The present results demonstrate that this acetylcholinesterase inhibitor has an ample cholinergic profile, which suggests a potential source of interest of (+/-)huprine X in Alzheimer's disease therapy.
ESTHER : Roman_2002_Neurosci.Lett_325_103
PubMedSearch : Roman_2002_Neurosci.Lett_325_103
PubMedID: 12044632

Title : Synthesis, in Vitro Pharmacology, and Molecular Modeling of syn-Huprines as Acetylcholinesterase Inhibitors - Camps_2001_J.Med.Chem_44_4733
Author(s) : Camps P , Gomez E , Munoz-Torrero D , Badia A , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 44 :4733 , 2001
Abstract : Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (+/-)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.
ESTHER : Camps_2001_J.Med.Chem_44_4733
PubMedSearch : Camps_2001_J.Med.Chem_44_4733
PubMedID: 11741490

Title : The pharmacology of novel acetylcholinesterase inhibitors, (+\/-)- huprines Y and X, on the Torpedo electric organ - Ros_2001_Eur.J.Pharmacol_421_77
Author(s) : Ros E , Aleu J , Gomez de Aranda I , Munoz-Torrero D , Camps P , Badia A , Marsal J , Solsona C
Ref : European Journal of Pharmacology , 421 :77 , 2001
Abstract : The effects of the tacrine-huperzine A hybrid acetylcholinesterase inhibitors, (+/-)-12-amino-3-chloro-9-methyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride ((+/-)-huprine Y) and (+/-)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride ((+/-)-huprine X), were tested on spontaneous synaptic activity by measuring the amplitude, the rise time, the rate of rise, the half-width and the area or the electrical charge of the miniature endplate potentials (m.e.p.ps) recorded extracellularly on Torpedo electric organ fragments. (+/-)-Huprine Y and (+/-)-huprine X at a concentration of 500 nM increased all the m.e.p.p. variables analyzed. The effect of (+/-)-huprine Y was smaller than that of (+/-)-huprine X for all the variables except for the rate of rise where there was no significant difference. The effects of these drugs were also tested on nicotinic receptors by analyzing the currents elicited by acetylcholine (100 microM) in Xenopus laevis oocytes, transplanted with membranes from Torpedo electric organ. Both drugs inhibited the currents in a reversible manner, (+/-)-huprine Y (IC(50)=452 nM) being more effective than (+/-)-huprine X (IC(50)=4865 nM). The Hill coefficient was 0.5 for both drugs. The inhibition of the nicotinic receptor was voltage-dependent and decreased at depolarizing potentials, and there was no significant difference in the effects between (+/-)-huprine Y and (+/-)-huprine X at concentrations near to their IC(50) values. At depolarizing potentials between -20 and +15 mV, these drugs did not have any detectable effect on the blockade of the nicotinic receptor. Both huprines increased the desensitization of the nicotinic receptors since the current closed quickly in the presence of the drugs, and there was no significant difference in this effect between (+/-)-huprine Y (500 nM) and (+/-)-huprine X (5 microM). We conclude that (+/-)-huprine Y and (+/-)-huprine X increase the level of acetylcholine in the synaptic cleft more effectively than tacrine. The interaction of (+/-)-huprine X with nicotinic receptors is weaker than that of (+/-)-huprine Y, suggesting that (+/-)-huprine X would be more specific to maintain the extracellular acetylcholine concentration.
ESTHER : Ros_2001_Eur.J.Pharmacol_421_77
PubMedSearch : Ros_2001_Eur.J.Pharmacol_421_77
PubMedID: 11399262

Title : Synthesis and acetylcholinesterase\/butyrylcholinesterase inhibition activity of new tacrine-like analogues - Marco_2001_Bioorg.Med.Chem_9_727
Author(s) : Marco JL , de los Rios C , Carreiras MC , Banos JE , Badia A , Vivas NM
Ref : Bioorganic & Medicinal Chemistry , 9 :727 , 2001
Abstract : The synthesis and preliminary results for acetylcholinesterase and butyrylcholinesterase inhibition activity of a series of pyrano[2,3-b]quinolines (2, 3) and benzonaphthyridines (5, 6) derivatives are described. These molecules are tacrine-like analogues which have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyrans and 6-amino-5-cyanopyridines]-3-carboxylates via Friedlander condensation with selected ketones. These compounds showed moderate acetylcholinesterase inhibition activity, the more potent (2e, 5b) being 6 times less active than tacrine. The butyrylcholinesterase activity of some of these molecules is also discussed.
ESTHER : Marco_2001_Bioorg.Med.Chem_9_727
PubMedSearch : Marco_2001_Bioorg.Med.Chem_9_727
PubMedID: 11310608

Title : N-Benzylpiperidine derivatives of 1,2,4-thiadiazolidinone as new acetylcholinesterase inhibitors - Martinez_2000_Eur.J.Med.Chem_35_913
Author(s) : Martinez A , Fernandez E , Castro A , Conde S , Rodriguez-Franco I , Banos JE , Badia A
Ref : Eur Journal of Medicinal Chemistry , 35 :913 , 2000
Abstract : A new family of 1,2,4-thiadiazolidinone derivatives containing the N-benzylpiperidine fragment has been synthesised. The acetylcholinesterase (AChE) inhibitory activity of all compounds was measured using Ellman's method and some of them turned out to be as potent as tacrine. Furthermore, compound 13 was as active as tacrine in reversing the blockade induced by tubocurarine at rat neuromuscular junction. Additionally, receptor binding studies provided new lead compounds for further development of alpha2-adrenergic and sigma-receptor antagonists. Molecular dynamic simulation using X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new compounds.
ESTHER : Martinez_2000_Eur.J.Med.Chem_35_913
PubMedSearch : Martinez_2000_Eur.J.Med.Chem_35_913
PubMedID: 11121617

Title : Synthesis of new N-(4-pyridyl)-1-aminopyrazoles and their muscarinic and adrenergic properties - Rodriguez-Franco_2000_Arch.Pharm.(Weinheim)_333_118
Author(s) : Rodriguez-Franco MI , Dorronsoro I , Martinez A , Perez C , Badia A , Banos JE
Ref : Arch Pharm (Weinheim) , 333 :118 , 2000
Abstract : The synthesis of new N-(4-pyridyl)-1-aminopyrazoles is described. Their binding properties were tested for muscarinic and other neurotransmitter receptors, together with their acetylcholinesterase inhibitory activity. The series derived from 3,5-dimethyl-1H-pyrazole showed moderate activities in both muscarinic and adrenergic receptor binding tests.
ESTHER : Rodriguez-Franco_2000_Arch.Pharm.(Weinheim)_333_118
PubMedSearch : Rodriguez-Franco_2000_Arch.Pharm.(Weinheim)_333_118
PubMedID: 10863795

Title : New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease - Camps_2000_J.Med.Chem_43_4657
Author(s) : Camps P , El Achab R , Morral J , Munoz-Torrero D , Badia A , Banos JE , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 43 :4657 , 2000
Abstract : Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.
ESTHER : Camps_2000_J.Med.Chem_43_4657
PubMedSearch : Camps_2000_J.Med.Chem_43_4657
PubMedID: 11101357

Title : Role of calcium on the modulation of spontaneous acetylcholine efflux by the D2 dopamine receptor subtype in rat striatal synaptosomes - Sanz_2000_Brain.Res_854_42
Author(s) : Sanz AG , Badia A , Clos MV
Ref : Brain Research , 854 :42 , 2000
Abstract : The role of calcium in the modulation of spontaneous [3H]acetylcholine ([3H]ACh) efflux through presynaptic D2 dopamine hetero-receptors was investigated in rat striatal synaptosomes. The kinetic studies of [3H]ACh efflux in the presence or absence of Ca2+ were carried out in nonstimulating conditions. When Ca2+ was omitted from the superfusion medium, a notable and significant (P<0.001) decrease of tritium efflux (39%) was obtained. While [3H]ACh efflux was insensitive to tetrodotoxin (TTX) 1 microM, cadmium (10 microM), a nonselective antagonist of calcium channels, significantly reduced the tritium efflux by 24% (P<0.001), while the L-type calcium antagonist, nifedipine, (30 microM) inhibited the tritium efflux by only 10% (P<0.02). 2-(4-Fenylpiperidine)cyclohexanol (vesamicol), an inhibitor of the vesicular [3H]ACh carrier, significantly depressed the spontaneous tritium efflux in the presence of Ca2+ (60%; P<0.001) and in a low-calcium medium (20%; P<0.001). Although 1 microM of 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT) inhibited spontaneous [3H]ACh efflux in the presence of calcium, this dopaminergic agonist did not modify the neurotransmitter release in either the low-Ca2+ medium or in the presence of vesamicol. These results suggest that the spontaneous [3H]ACh efflux is a process involving a Ca2+-dependent component (39%), sensitive to calcium channel-blockers and vesamicol, in rat striatal synaptosomes. In addition, activation of the D2 dopamine hetero-receptor only modulates the calcium-dependent component of spontaneous [3H]ACh efflux.
ESTHER : Sanz_2000_Brain.Res_854_42
PubMedSearch : Sanz_2000_Brain.Res_854_42
PubMedID: 10784105

Title : Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease - Camps_1999_J.Med.Chem_42_3227
Author(s) : Camps P , El Achab R , Gorbig DM , Morral J , Munoz-Torrero D , Badia A , Eladi Banos J , Vivas NM , Barril X , Orozco M , Luque FJ
Ref : Journal of Medicinal Chemistry , 42 :3227 , 1999
Abstract : Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.
ESTHER : Camps_1999_J.Med.Chem_42_3227
PubMedSearch : Camps_1999_J.Med.Chem_42_3227
PubMedID: 10464010

Title : Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease - Badia_1998_Bioorg.Med.Chem_6_427
Author(s) : Badia A , Banos JE , Camps P , Contreras J , Gorbig DM , Munoz-Torrero D , Simon M , Vivas NM
Ref : Bioorganic & Medicinal Chemistry , 6 :427 , 1998
Abstract : Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.
ESTHER : Badia_1998_Bioorg.Med.Chem_6_427
PubMedSearch : Badia_1998_Bioorg.Med.Chem_6_427
PubMedID: 9597187

Title : Action on noradrenergic transmission of an anticholinesterase: 9-amino-1,2,3,4-tetrahydroacridine - Vivas_1995_Neuropharmacol_34_367
Author(s) : Vivas NM , Marmol F , Salles J , Badia A , Dierssen M
Ref : Neuropharmacology , 34 :367 , 1995
Abstract : The mechanism by which 9-amino-1,2,3,4-tetrahydroacridine (THA) inhibits beta-adrenoceptor linked cyclic AMP formation and its possible relationship with the cholinergic system were studied. In addition, the effect of THA on alpha 1-adrenoceptor coupled transduction systems was also investigated. THA was not able to influence the concentration-response curve for forskolin indicating that it is not acting on the catalytic subunit of the adenylate cyclase complex. On the other hand a cholinergic component seems to participate in the action of THA on beta-adrenoceptor stimulated adenylate cyclase activity since the blockade of muscarinic receptors with atropine (10 microM) partially prevented the reduction in cyclic AMP formation attained by THA in the hippocampus, in isoprenaline-stimulated conditions. This effect is not reproducible by another potent anticholinesterase physostigmine. Moreover, THA at concentrations up to micromolar did not affect alpha 1-adrenoceptor stimulated cyclic AMP formation or phosphoinositide hydrolysis. In conclusion, the neuropharmacological profile of THA is not to be restricted to the cholinergic system and its effectiveness in improving age-associated cognitive deterioration may involve an action on the beta-adrenoceptor coupled signal transduction system. Moreover, the action of THA on the beta-adrenergic and cholinergic systems in the brain could be relevant to the amelioration of cognitive deterioration and could lead to the development of new therapeutic strategies.
ESTHER : Vivas_1995_Neuropharmacol_34_367
PubMedSearch : Vivas_1995_Neuropharmacol_34_367
PubMedID: 7566467

Title : Differential effects of physostigmine and 1,2,3,4-tetrahydro-9-aminoacridine on the beta-adrenoceptor transduction system - Vivas_1993_Eur.J.Pharmacol_245_9
Author(s) : Vivas NM , Badia A , Marmol F , Dierssen M
Ref : European Journal of Pharmacology , 245 :9 , 1993
Abstract : The effects of 1,2,3,4-tetrahydro-9-aminoacridine (THA) and physostigmine on beta-adrenoceptor-linked cyclic AMP accumulation have been analyzed in vitro in rat cortex and hippocampus. A 10-min incubation with increasing concentrations of THA reduced isoprenaline (10 microM)-stimulated cyclic AMP accumulation in a concentration-dependent manner in cortical (IC50 = 1.31 +/- 0.13 microM) and hippocampal (IC50 = 0.02 +/- 0.003 microM) structures. Conversely, physostigmine did not modify cyclic AMP synthesis in any experimental condition. The action of THA was non-competitive since it induced a non-parallel shift to the right of the concentration-response curve for isoprenaline. The differential effects of THA and physostigmine on the beta-adrenoceptor transduction system may account for the difference in their ability to restore cognitive function.
ESTHER : Vivas_1993_Eur.J.Pharmacol_245_9
PubMedSearch : Vivas_1993_Eur.J.Pharmacol_245_9
PubMedID: 8386672

Title : Comparative effects of velnacrine, tacrine and physostigmine on the twitch responses in the rat phrenic-hemidiaphragm preparation - Bosch_1993_Gen.Pharmacol_24_1101
Author(s) : Bosch F , Morales M , Badia A , Banos JE
Ref : General Pharmacology , 24 :1101 , 1993
Abstract : 1. Cholinesterase inhibitors potentiated twitch responses induced by nerve stimulation, with physostigmine more potent than tacrine and velnacrine. However, at higher concentrations, tacrine decreased twitch responses in a concentration-dependent manner. 2. Tacrine strongly depressed directly-induced twitch responses, whereas the other drugs had minimal effects. 3. Physostigmine was the most potent drug in reversal of tubocurarine-induced blockade, but its antagonism index was similar to those obtained with tacrine and velnacrine at higher concentrations. When evaluating their ability to reverse neomycin-induced blockade, all drugs exhibited a similar effect. 4. It is concluded that tacrine and velnacrine are less potent than physostigmine in potentiating skeletal neuromuscular transmission. Additionally, the blocking effects of tacrine could limit its therapeutic efficacy.
ESTHER : Bosch_1993_Gen.Pharmacol_24_1101
PubMedSearch : Bosch_1993_Gen.Pharmacol_24_1101
PubMedID: 8270168

Title : Post-train administration of 9-amino-1,2,3,4-tetrahydroacridine enhances passive avoidance retention and decreases beta-adrenoceptor-linked cyclic AMP formation in middle-aged rats - Dierssen_1992_Brain.Res_586_117
Author(s) : Dierssen M , Marmol F , Vivas NM , Clos MV , Badia A
Ref : Brain Research , 586 :117 , 1992
Abstract : The possible involvement of beta-adrenoceptor system in the effectiveness of 9-amino-1,2,3,4-tetrahydroacridine (THA) to attenuate retention deficits exhibited by middle-aged rats in a one-trial passive avoidance task has been investigated. THA (2.5 mg.kg-1), injected i.p. after training, induced a significant increase in test step-through latency (STL) in middle-aged rats. Post-training injection of THA reduced basal and isoprenaline stimulated cyclic AMP accumulation in cortex and hippocampus of every group of rats. It is suggested that the effect of THA on memory processes may involve an action on beta-adrenoceptor-linked cyclic AMP accumulation.
ESTHER : Dierssen_1992_Brain.Res_586_117
PubMedSearch : Dierssen_1992_Brain.Res_586_117
PubMedID: 1380875

Title : Effects of velnacrine, tacrine and physostigmine on tetanic twitch responses at the rat neuromuscular junction - Bosch_1992_Eur.J.Pharmacol_222_163
Author(s) : Bosch F , Morales M , Badia A , Banos JE
Ref : European Journal of Pharmacology , 222 :163 , 1992
Abstract : The effects of velnacrine (1-hydroxytacrine), tacrine and physostigmine on indirectly elicited twitch at low and high stimulation frequencies were analyzed in the rat phrenic hemidiaphragm preparation. At 0.2 Hz, velnacrine and physostigmine behaved in a similar manner, the latter showing a higher potentiating effect. This potentiation was observed at 3-100 microM velnacrine, whereas a slight depression appeared at higher concentrations. When tetanic responses were studied, the drug concentrations needed to depress tetanic tension and tetanic fade were quite different in the case of velnacrine (depression of tetanic tension from 1 microM and tetanic fade from 170 microM), whereas physostigmine and tacrine were able to affect these parameters at very similar concentrations. The results suggest that some effects of velnacrine could differ from those of tacrine in spite of the chemical similarity.
ESTHER : Bosch_1992_Eur.J.Pharmacol_222_163
PubMedSearch : Bosch_1992_Eur.J.Pharmacol_222_163
PubMedID: 1468493

Title : Acute effects of tetrahydroaminoacridine on beta-adrenoceptor-linked cyclic AMP accumulation in brain of young and middle-aged rats - Dierssen_1991_Neurosci.Lett_132_51
Author(s) : Dierssen M , Marmol F , Vivas NM , Clos MV , Gascon S , Badia A
Ref : Neuroscience Letters , 132 :51 , 1991
Abstract : The effects of acute treatment with 1,2,3,4-tetrahydro-9-aminoacridine (THA), a 4-aminopyridine derivative clinically effective in Alzheimer's disease, on beta-adrenoceptor-linked cyclic AMP accumulation have been investigated in cortical and hippocampal structures of young and middle-aged rats. In a first series of experiments, pretreatment with 2.5 mg/kg THA decreased basal cyclic AMP accumulation. When a phosphodiesterase inhibitor was added to the preparation, THA again decreased cyclic AMP levels in young rats, but failed to significantly modify cyclic AMP accumulation in middle-aged animals. Finally, in isoprenaline-stimulated conditions, acute treatment with tacrine was able to diminish cyclic AMP accumulation in every group of rats. It is suggested that the neurochemical action of THA in mammalian brain is more complex than earlier has been anticipated and may involve an action on beta-adrenoceptors.
ESTHER : Dierssen_1991_Neurosci.Lett_132_51
PubMedSearch : Dierssen_1991_Neurosci.Lett_132_51
PubMedID: 1724070