Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of new tacrine-like analogues

Marco, J. L.; Rı́os, Cristóbal de los; Carreiras, M. Carmo; Baños, Josep Eladi; Badı́a, Albert; Vivas, Nuria M.

doi:10.1016/s0968-0896(00)00284-4

Cited by 67 publications

(44 citation statements)

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“…In conclusion, ITH4012 is a new tacrine derivative that maintains its AChE-blocking activity (Marco et al, 2001) and, additionally, has neuroprotective properties against a variety of stimuli that have been implicated in the pathophysiology of AD. Whatever its ultimate neuroprotective mechanism might be, our data suggest that a mild calcium promotor that maintains a significant, yet modest, AChE inhibitory activity could be a new type of therapeutic target for treating patients of Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 95%

“…We were especially interested in derivatives that preserved their ability to inhibit AChE while possessing other properties, such as the modulation of voltage-dependent Ca 2ϩ channels and/or neuronal nicotinic receptors. As a result, we obtained a number of new compounds that were acceptable AChE inhibitors with the acquired additional properties (Marco et al, 2001;de los Ríos et al, 2002). One of these compounds, ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate (ITH4012) (Fig.…”

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confidence: 99%

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ITH4012 (Ethyl 5-Amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a Novel Acetylcholinesterase Inhibitor with “Calcium Promotor” and Neuroprotective Properties

Orozco¹,

Rı́os²,

Arias³

et al. 2004

J Pharmacol Exp Ther

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7,8,8] naphthyridine-3-carboxylate (ITH4012) is a novel tacrine derivative that can reduce cell death induced by various compounds with different mechanisms of action, such as thapsigargin (reticular stress), H 2 O 2 (free radicals), and veratridine (calcium overload), in bovine chromaffin cell. Cell viability, quantified as lactic dehydrogenase release, was significantly reduced by ITH4012 at concentrations ranging from 0.01 to 3 M. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid ␤ 25-35 -induced apoptosis, determined by flow cytometry. ITH4012 caused a slight elevation in the cytosolic concentration of Ca 2ϩ in fura 2-loaded bovine chromaffin cells, which could be related to the induction of protein synthesis relevant for cell survival. Blockade of protein synthesis by cycloheximide or blockade of Bcl-2's active site with HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) reversed the cytoprotective action of ITH4012. Furthermore, exposure of bovine chromaffin cells for 24 or 48 h to neuroprotective concentrations of this compound enhanced, nearly 3-fold, the expression of the antiapoptotic protein Bcl-2. In conclusion, ITH4012 is a tacrine derivative that maintains acetylcholinesterase-inhibiting activity (IC 50 ϭ 0.8 M) but has the additional property of acting as a calcium promotor, a property leading to neuroprotection through the induction of antiapoptotic proteins.Alzheimer's disease (AD) is a degenerative disorder of the central nervous system found primarily among the aged. It is the most common type of dementia in western societies and has been creating profound economic and social impacts as the elderly population continues to increase (Guttman et al., 1999). The hallmarks of the illness are extracellular deposition of neuritic plaques of amyloid-␤ peptide (A␤), intracellular formation of neurofibrillary tangles, and selective neuronal loss. Of all biochemical changes observed in AD patients, only the reduction in number of functional neuronal nicotinic receptors is related to neuropsychiatric symptoms (Schroder et al., 1991). For this reason, the only pharmacotherapeutical strategy that, until now, has proven to have some efficacy in slowing progression of the illness is that which improves cholinergic neurotransmission, counteracting the deficit of cerebral acetylcholine (Standaert and Young, 1996). Therefore, acetylcholinesterase inhibition is currently the therapeutic strategy most commonly used to treat Alzheimer's patients.On the other hand, moderate chronic depolarization has demonstrated an ability to increase the survival of different neuronal types. Also, there is evidence that this effect is mediated by the mild and sustained elevation of [Ca 2ϩ ] c ,

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

ITH4012 (Ethyl 5-Amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a Novel Acetylcholinesterase Inhibitor with “Calcium Promotor” and Neuroprotective Properties

Orozco¹,

Rı́os²,

Arias³

et al. 2004

J Pharmacol Exp Ther

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“…These sources are from the same lab (Marco-Contelles et al, 2006a;Marco et al, 2001;Leon et al, 2008;Marco et al, 2004;Leon et al, 2005). 3D-QSAR models have been built using CoMFA and CoMSIA methods, which contain both ligand-based QSAR and receptor-based QSAR.…”

Section: Data Setmentioning

confidence: 99%

3D-QSAR study of multi-target-directed AchE inhibitors based on autodocking

et al. 2010

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We do some research about multi-targetdirected AChE inhibitors of Tacrine-Nimodipine dihydropyridine. 3D-QSAR models have been built using CoMFA and CoMSIA methods, based on compounds which are very selective and potent AChEIs and show an excellent neuroprotective profile and a moderate Ca 2? channel blockade effect. These studies indicated that the QSAR models were statistically significant and high predictable (receptor-based research CoMFA model, q 2 = 0.686, r 2 = 0.948; CoMSIA model, q 2 = 0.756, r 2 = 0.907 in all of the models no. of components = 6). Consequently, based on these results, our models would offer help to better comprehend the structure-activity relationships existent for this class of compounds and also facilitate the design of novel inhibitors with good chemical property.

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“…Foi utilizado um conjunto de 53 inibidores de butirilcolinesterase (BuChE), derivados de tacrina e huprina, previamente descritos na literatura [22][23][24][25][26][27][28] …”

Section: Conjunto De Inibidoresunclassified

Estudos de QSAR 3D para um conjunto de inibidores de butirilcolinesterase humana

Freitas¹,

Paz²,

Castilho³

2009

Quím. Nova

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Recebido em 9/12/08; aceito em 14/4/09; publicado na web em 22/9/09 QSAR 3D STUDIES OF A SERIES OF HUMAN BUTYRYLCHOLINESTERASE INHIBITORS. Alzheimer's disease (AD) is considered the main cause of cognitive decline in adults. The available therapies for AD treatment seek to maintain the activity of cholinergic system through the inhibition of the enzyme acetylcholinesterase. However, butyrylcholinesterase (BuChE) can be considered an alternative target for AD treatment. Aiming at developing new BuChE inhibitors, robust QSAR 3D models with high predictive power were developed. INTRODUÇÃOA doença ou mal de Alzheimer (DA), descrita primeiramente por Alois Alzheimer 1 acomete cerca de 37 milhões de pessoas em todo o mundo, 2 sendo considerada a principal causa de declínio cognitivo em adultos.3 De fato, 50 a 70% dos casos de demência entre idosos acima de 65 anos está relacionada à DA e aproximadamente 5% desta população será afetada pelo mal de Alzheimer. 4 De acordo com a OMS, a prevalência da doença dobra a cada 5 anos, passando de 3% aos 70 anos para 20-30% aos 85 anos.3 Dessa forma, esperase que o número de casos aumente para 114 milhões até 2050.5 De fato, em função do número crescente de pacientes com DA, os custos diretos e indiretos associados ao tratamento dessa doença são de, no mínimo, 100 bilhões de dólares, nos EUA. 2O mal de Alzheimer caracteriza-se por diversos eventos metabólicos que culminam no aparecimento dos sinais característicos da doença. Entre esses eventos estão a deposição de placas de proteínas insolúveis b-Amiloides (Ab), como resultado do metabolismo anormal da proteína precursora de b-Amiloide (PPA) e formação de emaranhados neurofibrilares, em função do colapso do citoesqueleto neuronal, decorrente da hiperfosforilação da proteína Tau, em regiões do lobo temporal e neocórtex.6 Soma-se a isso, o processo de disfunção simpática e neuroquímica relacionada à redução da atividade colinérgica central. 7 Como consequência desses eventos neuropatológicos, há perda de memória, grandes variações de humor, depressão associada a distúrbios de linguagem, perda de poder de julgamento etc.Atualmente, as principais estratégias terapêuticas para o tratamento de DA baseiam-se na hipótese colinérgica ou na hipótese amiloide. De acordo com a hipótese colinérgica, processos neurodegenerativos levam à destruição de neurônios colinérgicos da região frontal do cérebro resultando em déficit da transmissão colinérgica central, 4 provocando declínio cognitivo e perda da capacidade de execução das tarefas diárias, redução da atenção e da memória.8-10 Segundo a hipótese da cascata amiloide, os níveis elevados de proteínas insolúveis b-Amiloides (Ab) são responsáveis pela formação de placas amiloides e emaranhados neurofibrilares que estão relacionados com morte celular, processos inflamatórios, demência e DA.11 Embora o desenvolvimento de fárma-cos que bloqueiem ou revertam a formação de proteínas insolúveis bAmiloides seja uma área de grande interesse, 12,13 as terapias disponíveis atualmente para o tratamento ...

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Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of new tacrine-like analogues

Cited by 67 publications

References 12 publications

ITH4012 (Ethyl 5-Amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a Novel Acetylcholinesterase Inhibitor with “Calcium Promotor” and Neuroprotective Properties

ITH4012 (Ethyl 5-Amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a Novel Acetylcholinesterase Inhibitor with “Calcium Promotor” and Neuroprotective Properties

3D-QSAR study of multi-target-directed AchE inhibitors based on autodocking

Estudos de QSAR 3D para um conjunto de inibidores de butirilcolinesterase humana

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