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[PMID]:29318278
[Au] Autor:Atri A; Frölich L; Ballard C; Tariot PN; Molinuevo JL; Boneva N; Windfeld K; Raket LL; Cummings JL
[Ad] Endereço:Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco.
[Ti] Título:Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials.
[So] Source:JAMA;319(2):130-142, 2018 01 09.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: New therapeutic approaches for Alzheimer disease (AD) are needed. Objective: To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Design, Setting, and Participants: Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Interventions: Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Main Outcomes and Measures: Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Results: Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. Conclusions and Relevance: In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. Trial Registration: clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Benzilaminas/uso terapêutico
Inibidores da Colinesterase/uso terapêutico
Indóis/uso terapêutico
Antagonistas da Serotonina/uso terapêutico
[Mh] Termos MeSH secundário: Acidentes por Quedas
Idoso
Idoso de 80 Anos ou mais
Doença de Alzheimer/psicologia
Benzilaminas/administração & dosagem
Benzilaminas/efeitos adversos
Inibidores da Colinesterase/efeitos adversos
Cognição/efeitos dos fármacos
Relação Dose-Resposta a Droga
Método Duplo-Cego
Quimioterapia Combinada
Feminino
Galantamina/uso terapêutico
Seres Humanos
Indanos/uso terapêutico
Indóis/administração & dosagem
Indóis/efeitos adversos
Masculino
Meia-Idade
Piperidinas/uso terapêutico
Rivastigmina/uso terapêutico
Antagonistas da Serotonina/administração & dosagem
Antagonistas da Serotonina/efeitos adversos
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 ((2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine); 0 (Benzylamines); 0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Indoles); 0 (Piperidines); 0 (Serotonin Antagonists); 0D3Q044KCA (Galantamine); 8SSC91326P (donepezil); PKI06M3IW0 (Rivastigmine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180111
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.20373


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[PMID]:29339253
[Au] Autor:Xiao X; Zhang XX; Zhan MM; Cheng K; Li S; Xie Z; Liao C
[Ad] Endereço:School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
[Ti] Título:Design, synthesis and bioevalucation of novel 2,3-dihydro-1H-inden-1-amine derivatives as potent and selective human monoamine oxidase B inhibitors based on rasagiline.
[So] Source:Eur J Med Chem;145:588-593, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH -, -SCH -, -OCH CH -, -OCH CH O-, -OCH CH CH O- were tried. A promising selective hMAO-B inhibitor D14 with similar inhibitory activity as rasagiline and improved isoform selectivity was yielded. The selectivity profile of compounds reported herein suggests that we can further develop more potent hMAO-B inhibitors with high isoform selectivity through this strategy.
[Mh] Termos MeSH primário: Aminas/farmacologia
Desenho de Drogas
Indanos/farmacologia
Indenos/farmacologia
Inibidores da Monoaminoxidase/farmacologia
Monoaminoxidase/metabolismo
[Mh] Termos MeSH secundário: Aminas/síntese química
Aminas/química
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Seres Humanos
Indanos/química
Indenos/síntese química
Indenos/química
Modelos Moleculares
Estrutura Molecular
Inibidores da Monoaminoxidase/síntese química
Inibidores da Monoaminoxidase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amines); 0 (Indans); 0 (Indenes); 0 (Monoamine Oxidase Inhibitors); 003N66TS6T (rasagiline); EC 1.4.3.4 (Monoamine Oxidase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE


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[PMID]:29192699
[Au] Autor:Kim J; Kim I
[Ad] Endereço:College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea. ikyonkim@yonsei.ac.kr.
[Ti] Título:Design and synthesis of a hybrid framework of indanone and chromane: total synthesis of a homoisoflavanoid, brazilane.
[So] Source:Org Biomol Chem;16(1):89-100, 2017 Dec 19.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A chemical backbone of tetracyclic homoisoflavanoid natural products such as brazilin inspired us to design a new chemical scaffold, 6a,11b-dihydroindeno[2,1-c]chromen-7(6H)-one, which is a hybrid structure of indanone and chromane. Pd-catalyzed Suzuki-Miyaura cross-coupling of 4-chloro-2H-chromene-3-carbaldehydes with (hetero)aryl boronic acids was employed as a means to introduce a wide variety of (hetero)aryl groups as the D ring and intramolecular Friedel-Crafts acylation was utilized to construct the C ring of this skeleton. Total synthesis of the natural product, brazilane, was also demonstrated via this new chemical framework.
[Mh] Termos MeSH primário: Produtos Biológicos/síntese química
Cromanos/química
Desenho de Drogas
Flavonoides/síntese química
Indanos/química
Isoflavonas/síntese química
[Mh] Termos MeSH secundário: Produtos Biológicos/química
Flavonoides/química
Isoflavonas/química
Estrutura Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biological Products); 0 (Chromans); 0 (Flavonoids); 0 (Indans); 0 (Isoflavones); 0 (brazilane); B926Y9U4QN (indacrinone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob02758c


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[PMID]:29358689
[Au] Autor:Gueye M; Manathunga M; Agathangelou D; Orozco Y; Paolino M; Fusi S; Haacke S; Olivucci M; Léonard J
[Ad] Endereço:Université de Strasbourg, CNRS, Institut de Physique et Chimie des Matériaux de Strasbourg, UMR 7504, F-67034, Strasbourg, France.
[Ti] Título:Engineering the vibrational coherence of vision into a synthetic molecular device.
[So] Source:Nat Commun;9(1):313, 2018 01 22.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The light-induced double-bond isomerization of the visual pigment rhodopsin operates a molecular-level optomechanical energy transduction, which triggers a crucial protein structure change. In fact, rhodopsin isomerization occurs according to a unique, ultrafast mechanism that preserves mode-specific vibrational coherence all the way from the reactant excited state to the primary photoproduct ground state. The engineering of such an energy-funnelling function in synthetic compounds would pave the way towards biomimetic molecular machines capable of achieving optimum light-to-mechanical energy conversion. Here we use resonance and off-resonance vibrational coherence spectroscopy to demonstrate that a rhodopsin-like isomerization operates in a biomimetic molecular switch in solution. Furthermore, by using quantum chemical simulations, we show why the observed coherent nuclear motion critically depends on minor chemical modifications capable to induce specific geometric and electronic effects. This finding provides a strategy for engineering vibrationally coherent motions in other synthetic systems.
[Mh] Termos MeSH primário: Materiais Biomiméticos/química
Indanos/química
Dispositivos Ópticos
Pirróis/química
Retinaldeído/química
Rodopsina/química
[Mh] Termos MeSH secundário: Alquilação
Animais
Materiais Biomiméticos/síntese química
Engenharia Química
Seres Humanos
Indanos/síntese química
Luz
Processos Fotoquímicos
Pirróis/síntese química
Teoria Quântica
Análise Espectral/instrumentação
Análise Espectral/métodos
Vibração
Visão Ocular/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Indans); 0 (Pyrroles); 9009-81-8 (Rhodopsin); RR725D715M (Retinaldehyde)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180124
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02668-w


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[PMID]:27773686
[Au] Autor:Hsu CW; Hsieh JH; Huang R; Pijnenburg D; Khuc T; Hamm J; Zhao J; Lynch C; van Beuningen R; Chang X; Houtman R; Xia M
[Ad] Endereço:NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
[Ti] Título:Differential modulation of FXR activity by chlorophacinone and ivermectin analogs.
[So] Source:Toxicol Appl Pharmacol;313:138-148, 2016 12 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs.
[Mh] Termos MeSH primário: Indanos/farmacologia
Ivermectina/farmacologia
Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células HEK293
Seres Humanos
Ivermectina/análogos & derivados
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Indans); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 34Y6E0063Y (chlorophacinone); 70288-86-7 (Ivermectin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180124
[Lr] Data última revisão:
180124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29284465
[Au] Autor:Jia Y; Zhang X; Yu J; Han J; Yu T; Shi J; Zhao L; Nie K
[Ad] Endereço:First Teaching Hospital of Tianjin University of Traditional ChineseMedicine, Tianjin, 300193, China.
[Ti] Título:Acupuncture for patients with mild to moderate Alzheimer's disease: a randomized controlled trial.
[So] Source:BMC Complement Altern Med;17(1):556, 2017 Dec 29.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. However, none of medical treatment can stop or reverse the underlying neurodegenerative of AD at present. Acupuncture has attracted more and more attention in recent years due to its efficacy and very few side effects. Lately, a systematic review has thought that the evidence on the effectiveness of acupuncture in improving the cognitive function of AD patients was not powerful enough. Therefore, the aim of this study is to explore the efficacy and safety of acupuncture in patients with mild to moderate AD. METHODS: This was a randomized, controlled, parallel-group, exploratory study with 4-week baseline (T0), 12-week treatment phase (T1) and 12-week follow-up period (T2). Patients with mild to moderate AD meeting the included criteria were randomly allocated into either acupuncture or donepezil hydrochloride groups. The acupuncture group(AG) was given acupuncture treatment three times per week and the donepezil hydrochloride group(DG) group was administered donepezil hydrochloride once daily (5 mg/day for the first 4 weeks and 10 mg/day thereafter). Primary efficacy was measured using Alzheimer's disease Assessment Scale-Cognitive (ADAS-cog) and Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus). The second outcomes were measured with 23-Item Alzheimer's disease Cooperative Study Activities of Daily Living Scales (ADAS-ADL ) and Neuropsychiatric Index (NPI). RESULTS: Of 87 participants enrolled in the study, 79 patients finished their treatment and follow-up processes. The ADAS-cog scores for AG group showed obvious decreases at T2 and ∆(T2-T0)when compared with DG group, and significant between-group differences were detected (all p < 0.05). The mean CIBIC-Plus values for the AG group at T1 and T2 were much lower than that for the DG group, and there were significant differences between the two groups (푃<0.05). There were no significant between-group differences in the scores of ADAS-ADL and NPI during the study period. Treatment discontinuations due to adverse events were 0 (0%) and 4 (9.09%) for the AG and DG groups, respectively. CONCLUSIONS: Acupuncture is safe, well tolerated and effective in improving the cognitive function, global clinical status of AD. TRIAL REGISTRATION: ChiCTR-IOR-17010465 (Retroactively registered on 18 JAN 2017).
[Mh] Termos MeSH primário: Terapia por Acupuntura
Doença de Alzheimer/terapia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Doença de Alzheimer/fisiopatologia
Feminino
Seres Humanos
Indanos
Masculino
Testes de Estado Mental e Demência
Piperidinas
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Indans); 0 (Piperidines); 8SSC91326P (donepezil)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-2064-x


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[PMID]:29261656
[Au] Autor:Weed MR; Polino J; Signor L; Bookbinder M; Keavy D; Benitex Y; Morgan DG; King D; Macor JE; Zaczek R; Olson R; Bristow LJ
[Ad] Endereço:Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Company, Wallingford, CT, United States of America.
[Ti] Título:Nicotinic alpha 7 receptor agonists EVP-6124 and BMS-933043, attenuate scopolamine-induced deficits in visuo-spatial paired associates learning.
[So] Source:PLoS One;12(12):e0187609, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.
[Mh] Termos MeSH primário: Aprendizagem por Associação de Pares/efeitos dos fármacos
Quinuclidinas/farmacologia
Percepção Espacial/classificação
Compostos de Espiro/farmacologia
Tiofenos/farmacologia
Percepção Visual/efeitos dos fármacos
Receptor Nicotínico de Acetilcolina alfa7/agonistas
[Mh] Termos MeSH secundário: Animais
Indanos/farmacologia
Macaca fascicularis
Masculino
Piperidinas/farmacologia
Quinuclidinas/química
Tempo de Reação/efeitos dos fármacos
Hidrobrometo de Escopolamina
Compostos de Espiro/química
Análise e Desempenho de Tarefas
Tiofenos/química
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-chloro-N-quinuclidin-3-yl-benzo(b)thiophene-2-carboxamide); 0 (BMS-933043); 0 (Indans); 0 (Piperidines); 0 (Quinuclidines); 0 (Spiro Compounds); 0 (Thiophenes); 0 (alpha7 Nicotinic Acetylcholine Receptor); 451IFR0GXB (Scopolamine Hydrobromide); 8SSC91326P (donepezil)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187609


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[PMID]:29195794
[Au] Autor:Piplani P; Jain A; Devi D; Anjali; Sharma A; Silakari P
[Ad] Endereço:University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India. Electronic address: ppvohra28in@pu.ac.in.
[Ti] Título:Design, synthesis and pharmacological evaluation of some novel indanone derivatives as acetylcholinesterase inhibitors for the management of cognitive dysfunction.
[So] Source:Bioorg Med Chem;26(1):215-224, 2018 01 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The present study reports the effect of indanone derivatives on scopolamine induced deficit cholinergic neurotransmission serving as promising leads for the therapeutics of cognitive dysfunction. Eleven compounds 54-64 have been designed, synthesised and evaluated against behavioural alterations using step down passive avoidance protocol at a dose of 0.5 mg/kg with Donepezil (1) as the reference standard. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Compounds 54, 56, 59 and 64 displayed appreciable activity with an IC value of 14.06 µM, 12.30 µM, 14.06 µM and 12.01 µM, respectively towards acetylcholinesterase inhibition. The molecular docking study performed to predict the binding mode of the compounds suggested that these compounds could bind appreciably to the amino acids present at the active site of recombinant human acetylcholinesterase (rhAChE). The behavioural, biochemical and in silico pharmacokinetic studies were in concordance with each other.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Aprendizagem da Esquiva/efeitos dos fármacos
Inibidores da Colinesterase/farmacologia
Disfunção Cognitiva/tratamento farmacológico
Desenho de Drogas
Indanos/farmacologia
[Mh] Termos MeSH secundário: Animais
Inibidores da Colinesterase/administração & dosagem
Inibidores da Colinesterase/química
Disfunção Cognitiva/induzido quimicamente
Disfunção Cognitiva/metabolismo
Relação Dose-Resposta a Droga
Feminino
Indanos/administração & dosagem
Indanos/química
Camundongos
Simulação de Acoplamento Molecular
Estrutura Molecular
Hidrobrometo de Escopolamina
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Indans); 451IFR0GXB (Scopolamine Hydrobromide); B926Y9U4QN (indacrinone); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180106
[Lr] Data última revisão:
180106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


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[PMID]:28458424
[Au] Autor:Pattanashetti LA; Taranalli AD; Parvatrao V; Malabade RH; Kumar D
[Ad] Endereço:Department of Pharmacology, K.L.E. University's, College of Pharmacy, Belgaum, Karnataka, India.
[Ti] Título:Evaluation of neuroprotective effect of quercetin with donepezil in scopolamine-induced amnesia in rats.
[So] Source:Indian J Pharmacol;49(1):60-64, 2017 Jan-Feb.
[Is] ISSN:1998-3751
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The objective of this study was to evaluate the neuroprotective effect of quercetin with donepezil in scopolamine-induced amnesia in rats. MATERIALS AND METHODS: Five groups of adult male Wistar rats (12 months old) weighing 180-200 g ( = 6) were used. The normal control group received normal saline and test group animals were pretreated orally with quercetin (25 mg/kg), donepezil (3 mg/kg), and a combination of quercetin (25 mg/kg) with donepezil (3 mg/kg), respectively, dosed at every 24 h interval for 14 consecutive days, afterward amnesia was induced by scopolamine (3 mg/kg) on the 14 day through intraperitoneal route. Cognitive performance was assessed by the Morris water maze, elevated plus maze, and passive avoidance paradigm. Acetylcholinesterase enzyme (AchE) level, biochemical markers such as lipid peroxidase (LPO), glutathione (GSH), ß amyloid level, and histopathological study of rat brain were estimated. Statistical analysis was done by one-way analysis of variance, followed by Dunnett's test. ≥ 0.05 was considered statistically significant. RESULTS: Pretreatment with quercetin, donepezil, and their combination showed a significant increase in escape latency, step-through latency, and decreased transfer latency in respective cognitive models of the Morris water maze, passive avoidance test, and elevated plus maze. Further coadministration significantly decreased AchE level, ß amyloid level as compared to individual therapy. Biochemical markers such as elevated GSH, decreased LPO were observed, and histopathological studies revealed the reversal of neuronal damage in the treatment group ( < 0.05) as compared to scopolamine-treated control group. CONCLUSION: Pretreatment with quercetin potentiates the action of donepezil in scopolamine-induced amnesia in rats. The improved cognitive memory could be due to the synergistic effect of the drugs by decreasing AchE level, ß amyloid level, and antioxidant action in rat brain.
[Mh] Termos MeSH primário: Amnésia/prevenção & controle
Indanos/farmacologia
Fármacos Neuroprotetores/farmacologia
Piperidinas/farmacologia
Quercetina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antioxidantes/administração & dosagem
Antioxidantes/farmacologia
Aprendizagem da Esquiva/efeitos dos fármacos
Cognição/efeitos dos fármacos
Modelos Animais de Doenças
Sinergismo Farmacológico
Indanos/administração & dosagem
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Memória/efeitos dos fármacos
Fármacos Neuroprotetores/administração & dosagem
Nootrópicos/administração & dosagem
Nootrópicos/farmacologia
Piperidinas/administração & dosagem
Quercetina/administração & dosagem
Ratos
Ratos Wistar
Hidrobrometo de Escopolamina/toxicidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Indans); 0 (Neuroprotective Agents); 0 (Nootropic Agents); 0 (Piperidines); 451IFR0GXB (Scopolamine Hydrobromide); 8SSC91326P (donepezil); 9IKM0I5T1E (Quercetin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.4103/0253-7613.201016


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[PMID]:28454848
[Au] Autor:Yan J; Hu J; Liu A; He L; Li X; Wei H
[Ad] Endereço:School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
[Ti] Título:Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin.
[So] Source:Bioorg Med Chem;25(12):2946-2955, 2017 06 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC =187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aß self-aggregation at 20µM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Peptídeos beta-Amiloides/metabolismo
Inibidores da Colinesterase/farmacologia
Curcumina/farmacologia
Indanos/farmacologia
Fragmentos de Peptídeos/metabolismo
Piperidinas/farmacologia
Agregados Proteicos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Doença de Alzheimer/enzimologia
Doença de Alzheimer/metabolismo
Animais
Barreira Hematoencefálica/metabolismo
Inibidores da Colinesterase/química
Inibidores da Colinesterase/farmacocinética
Curcumina/análogos & derivados
Curcumina/farmacocinética
Desenho de Drogas
Electrophorus
Seres Humanos
Indanos/química
Indanos/farmacocinética
Ligantes
Simulação de Acoplamento Molecular
Terapia de Alvo Molecular
Piperidinas/química
Piperidinas/farmacocinética
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Ligands); 0 (Peptide Fragments); 0 (Piperidines); 0 (Protein Aggregates); 0 (amyloid beta-protein (1-42)); 8SSC91326P (donepezil); EC 3.1.1.7 (Acetylcholinesterase); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE



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