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  1 / 2083 MEDLINE  
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[PMID]:26708634
[Au] Autor:Misik J; Korabecny J; Nepovimova E; Kracmarova A; Kassa J
[Ad] Endereço:University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. Electronic address: misik@pmfhk.cz.
[Ti] Título:Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats--Is there a potential for Alzheimer's disease treatment?
[So] Source:Neurosci Lett;612:261-268, 2016 Jan 26.
[Is] ISSN:1872-7972
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Inibidores da Colinesterase/farmacologia
Transtornos Cognitivos/tratamento farmacológico
Antagonistas Muscarínicos
Quinuclidinil Benzilato
Tacrina/análogos & derivados
Tacrina/farmacologia
[Mh] Termos MeSH secundário: Animais
Aprendizagem da Esquiva/efeitos dos fármacos
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/uso terapêutico
Transtornos Cognitivos/induzido quimicamente
Transtornos Cognitivos/psicologia
Indanos/farmacologia
Indanos/uso terapêutico
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Piperidinas/farmacologia
Piperidinas/uso terapêutico
Ratos Wistar
Tacrina/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Muscarinic Antagonists); 0 (Piperidines); 4VX7YNB537 (Tacrine); 6581-06-2 (Quinuclidinyl Benzilate); 8SSC91326P (donepezil)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170815
[Lr] Data última revisão:
170815
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151229
[St] Status:MEDLINE


  2 / 2083 MEDLINE  
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[PMID]:26428990
[Au] Autor:Rydzewski J; Nowak W
[Ad] Endereço:Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Grudziadzka 5, 87-100 Torun, Poland.
[Ti] Título:Memetic algorithms for ligand expulsion from protein cavities.
[So] Source:J Chem Phys;143(12):124101, 2015 Sep 28.
[Is] ISSN:1089-7690
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper, two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics (MD) and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic G-protein-coupled receptor, enzyme nitrile hydratase, and heme-protein cytochrome P450cam. In these cases, the memetic methods outperform simulated annealing and random acceleration molecular dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a network of channels is studied.
[Mh] Termos MeSH primário: Algoritmos
Cânfora 5-Mono-Oxigenase/metabolismo
Hidroliases/metabolismo
Ligantes
Simulação de Dinâmica Molecular
Receptor Muscarínico M2/metabolismo
[Mh] Termos MeSH secundário: Cânfora/química
Cobalto/química
Difusão
Heme/metabolismo
Niacinamida/química
Ligação Proteica
Quinuclidinil Benzilato/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (Receptor, Muscarinic M2); 25X51I8RD4 (Niacinamide); 3G0H8C9362 (Cobalt); 42VZT0U6YR (Heme); 6581-06-2 (Quinuclidinyl Benzilate); 76-22-2 (Camphor); EC 1.14.15.1 (Camphor 5-Monooxygenase); EC 4.2.1.- (Hydro-Lyases); EC 4.2.1.- (nitrile hydratase)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151002
[Lr] Data última revisão:
151002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151003
[St] Status:MEDLINE
[do] DOI:10.1063/1.4931181


  3 / 2083 MEDLINE  
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[PMID]:26053513
[Au] Autor:Alfonzo MJ; Alfonzo RG; Alfonzo González M; de Becemberg IL
[Ad] Endereço:a Facultad de Medicina, Sección de Biomembranas , Instituto de Medicina Experimental (IME), Universidad Central de Venezuela , Sabana Grande, Caracas , Venezuela.
[Ti] Título:Muscarinic drugs regulate the PKG-II-dependent phosphorylation of M3 muscarinic acetylcholine receptors at plasma membranes from airway smooth muscle.
[So] Source:J Recept Signal Transduct Res;35(4):319-28, 2015.
[Is] ISSN:1532-4281
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Muscarinic agonists induce the activation of the airway smooth muscle (ASM) leading to smooth muscle contraction, important in asthma. This activation is mediated through M2/M3 muscarinic acetylcholine receptors (mAChRs). Muscarinic receptor activity, expressed as [(3)H]QNB binding at plasma membranes from bovine tracheal smooth muscle (BTSM), increased with cGMP and was augmented significantly cGMP plus ATP but diminished with the PKG-II inhibitor, Sp-8-pCPT-cGMPS. The [(3)H]-QNB binding was accelerated by okadaic acid, (OKA), a protein phosphatase (PPase) inhibitor. These two results indicated the involvement of a membrane-bound PPase. Moreover, a cGMP-dependent-[(32)P]γATP phosphorylation of plasma membranes from BTSM was stimulated at low concentrations of muscarinic agonist carbamylcholine (CC). However, higher amounts of CC produced a significant decrement of [(32)P]-labeling. A selective M3mAChR antagonist, 4-DAMP produced a dramatic inhibition of the basal and CC-dependent [(32)P]-labeling. The [(32)P] labeled membrane sediments were detergent solubilized and immunoprecipitated with specific M2/M3mAChR antibodies. The M3mAChR immuno-precipitates exhibited the highest cGMP-dependent [(32)P]-labeling, indicating it is a PKG-II substrate. Experiments using synthetic peptides from the C-terminal of the third intracellular loop (i3) of both M2mAChR (356-369) and M3mAChR (480-493) as external PKG-II substrates resulted in the i3M3-peptide being heavily phosphorylated. These results indicated that PKG-II phosphorylated the M3mAChR at the i3M3 domain ((480)MSLIKEKK(485)), suggesting that Ser(481) may be the target. Finally, this phosphorylation site seems to be regulated by a membrane-bound PPase linked to muscarinic receptor. These findings are important to understand the role of M3mAChR in the patho-physiology of ASM involved in asthma and COPD.
[Mh] Termos MeSH primário: Proteínas Quinases Dependentes de GMP Cíclico/metabolismo
Agonistas Muscarínicos/farmacologia
Antagonistas Muscarínicos/farmacologia
Músculo Liso/efeitos dos fármacos
Músculo Liso/metabolismo
Receptor Muscarínico M3/metabolismo
[Mh] Termos MeSH secundário: Animais
Asma/etiologia
Asma/fisiopatologia
Bovinos
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
GMP Cíclico/análogos & derivados
GMP Cíclico/metabolismo
GMP Cíclico/farmacologia
Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores
Retroalimentação Fisiológica
Seres Humanos
Técnicas In Vitro
Agonistas Muscarínicos/metabolismo
Antagonistas Muscarínicos/metabolismo
Fosforilação
Inibidores de Proteínas Quinases/farmacologia
Quinuclidinil Benzilato/metabolismo
Quinuclidinil Benzilato/farmacocinética
Transdução de Sinais/efeitos dos fármacos
Tionucleotídeos/farmacologia
Traqueia/efeitos dos fármacos
Traqueia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate); 0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Protein Kinase Inhibitors); 0 (Receptor, Muscarinic M3); 0 (Thionucleotides); 6581-06-2 (Quinuclidinyl Benzilate); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:151020
[Lr] Data última revisão:
151020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150609
[St] Status:MEDLINE
[do] DOI:10.3109/10799893.2014.982826


  4 / 2083 MEDLINE  
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[PMID]:25745976
[Au] Autor:Moezi L; Pirsalami F; Inaloo S
[Ad] Endereço:Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
[Ti] Título:Constipation enhances the propensity to seizure in pentylenetetrazole-induced seizure models of mice.
[So] Source:Epilepsy Behav;44:200-6, 2015 Mar.
[Is] ISSN:1525-5069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epilepsy is characterized by spontaneous recurrent seizures and represents one of the most frequent neurological diseases, affecting about 60 million people worldwide. The cellular and neurocircuit bases of epilepsy are poorly understood. Constipation is a common gastrointestinal disorder characterized by symptoms such as straining, hard stool, and infrequent defecation. Population-based studies have shown that the prevalence of constipation is up to 30% of the population in developed countries. The causal link between seizure and constipation is a common belief among patients and physicians, but there are no scientific data to support this association. The current investigation evaluated the effects of constipation induced by loperamide (a peripheral µ-opioid receptor agonist without effect on central nervous system receptors) and clidinium (a quaternary amine antimuscarinic agent with reduced central nervous system effects) on two different seizure models of mice: (1) myoclonic, clonic, and generalized tonic seizures and death induced by intraperitoneal administration of pentylenetetrazole and (2) clonic seizure threshold induced by intravenous infusion of pentylenetetrazole. We demonstrated that the measured intestinal transit (%intestinal transit) decreased after loperamide or clidinium treatment for 3days. Constipation in mice which was induced by loperamide or clonidine caused a decrease in threshold to clonic seizure in the intravenous pentylenetetrazole seizure model. Moreover loperamide- or clidinium-induced constipation decreased latencies to, clonic, and tonic seizures and death in the intraperitoneal pentylenetetrazole model of mice. Serum ammonia levels were slightly elevated in both loperamide- and clidinium-treated mice. In conclusion, loperamide- or clidinium-induced constipated mice are more prone to seizure which might confirm the belief of patients and physicians about constipation as a trigger of seizure.
[Mh] Termos MeSH primário: Constipação Intestinal/complicações
Convulsivantes/toxicidade
Pentilenotetrazol/toxicidade
Convulsões/induzido quimicamente
[Mh] Termos MeSH secundário: Animais
Antidiarreicos/toxicidade
Constipação Intestinal/induzido quimicamente
Modelos Animais de Doenças
Interações Medicamentosas
Trânsito Gastrointestinal
Injeções Intraperitoneais
Loperamida/toxicidade
Masculino
Camundongos
Parassimpatolíticos/toxicidade
Quinuclidinil Benzilato/análogos & derivados
Quinuclidinil Benzilato/toxicidade
Convulsões/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidiarrheals); 0 (Convulsants); 0 (Parasympatholytics); 6581-06-2 (Quinuclidinyl Benzilate); 6X9OC3H4II (Loperamide); BO76JF850N (clidinium); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1511
[Cu] Atualização por classe:150420
[Lr] Data última revisão:
150420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150310
[St] Status:MEDLINE


  5 / 2083 MEDLINE  
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[PMID]:25690521
[Au] Autor:Misik J; Korabecny J; Nepovimova E; Cabelova P; Kassa J
[Ad] Endereço:Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
[Ti] Título:The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test.
[So] Source:Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub;159(4):547-53, 2015 Dec.
[Is] ISSN:1213-8118
[Cp] País de publicação:Czech Republic
[La] Idioma:eng
[Ab] Resumo:AIMS: The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil. METHODS: Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method. RESULTS: QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. CONCLUSION: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.
[Mh] Termos MeSH primário: Comportamento Animal/efeitos dos fármacos
Inibidores da Colinesterase/farmacologia
Indanos/farmacologia
Nootrópicos/farmacologia
Piperidinas/farmacologia
Quinuclidinil Benzilato/toxicidade
Tacrina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Antagonistas Muscarínicos/toxicidade
Ratos Wistar
Tacrina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Indans); 0 (Muscarinic Antagonists); 0 (Nootropic Agents); 0 (Piperidines); 4VX7YNB537 (Tacrine); 6581-06-2 (Quinuclidinyl Benzilate); 8SSC91326P (donepezil)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150219
[St] Status:MEDLINE
[do] DOI:10.5507/bp.2015.006


  6 / 2083 MEDLINE  
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[PMID]:25450763
[Au] Autor:Kashyap M; Mulsant BH; Tannenbaum C
[Ad] Endereço:Faculty of Pharmacy, AIMST University, Semeling, Malaysia. Electronic address: avi_mandu@yahoo.co.in.
[Ti] Título:Small longitudinal study of serum anticholinergic activity and cognitive change in community-dwelling older adults.
[So] Source:Am J Geriatr Psychiatry;23(3):326-9, 2015 Mar.
[Is] ISSN:1545-7214
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The discriminative ability of serum anticholinergic activity (SAA) to differentiate between older individuals with stable versus deteriorating cognition remains undetermined. We examined the relationship between SAA changes, the presence or absence of a mild neurocognitive disorder, age and anticholinergic medication over a one-year time period. METHODS: SAA at baseline and one-year follow-up was measured for 121 older adults without dementia. Participants were classified at both timepoints as being cognitively intact or meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a mild neurocognitive disorder. Medications were assessed according to the Anticholinergic Cognitive Burden (ACB) scale. RESULTS: SAA changes did not discriminate between individuals whose cognition remained stable versus those with improvement or decline (H[3]=0.725, p=0.867). SAA change did not vary between age groups, and could not reliably differentiate between individuals on ACB medication or not. CONCLUSION: While SAA does not appear to be a valid biomarker for cognitive decline, longitudinal studies with a larger sample size and longer duration are required to confirm this finding.
[Mh] Termos MeSH primário: Antagonistas Colinérgicos/sangue
Disfunção Cognitiva/sangue
Disfunção Cognitiva/diagnóstico
[Mh] Termos MeSH secundário: Idoso
Biomarcadores/sangue
Estudos de Casos e Controles
Feminino
Seres Humanos
Estudos Longitudinais
Masculino
Quinuclidinil Benzilato
Ensaio Radioligante
Distribuição Espacial da População
Trítio
Incontinência Urinária/sangue
Incontinência Urinária/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 0 (Cholinergic Antagonists); 10028-17-8 (Tritium); 6581-06-2 (Quinuclidinyl Benzilate)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


  7 / 2083 MEDLINE  
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[PMID]:24632008
[Au] Autor:Misik J; Vanek J; Musilek K; Kassa J
[Ad] Endereço:Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Electronic address: misik@pmfhk.cz.
[Ti] Título:Cholinergic antagonist 3-quinuclidinyl benzilate - Impact on learning and memory in Wistar rats.
[So] Source:Behav Brain Res;266:193-200, 2014 Jun 01.
[Is] ISSN:1872-7549
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:3-Quinuclidinyl benzilate (QNB) represents a non-selective, competitive antagonist of cholinergic receptors, which has been previously used to generate cognitive deficits in animal models of neurodegenerative disorders. The aim of this study was evaluation of QNB potency for creation of cognitive impairment during the acquisition, consolidation and retrieval stages of learning and memory in rats. Male Wistar rats were subjected to a water maze task with hidden platform and a step-through passive avoidance task. The water maze test was carried out in two separate experiments focused on spatial learning (acquisition test) and long-term spatial memory (retrieval test). QNB doses (0.5, 1.0, 2.0 and 5.0 mg kg(-1)) were administered to rats intraperitoneally before training sessions (acquisition test) or before probe trial (retrieval test). A QNB dose of 2.0 mg kg(-1) was administered to rats in the passive avoidance task before training (acquisition test), immediately post-training (consolidation test) or 24h pre-retention (retrieval test). QNB significantly impaired the acquisition in the water maze at doses 0.5-5.0 mg kg(-1) as well as the acquisition of passive avoidance task. In contrast, consolidation and retrieval were not affected by QNB, indicating that QNB specifically affects the stage of acquisition.
[Mh] Termos MeSH primário: Transtornos de Aprendizagem/induzido quimicamente
Rememoração Mental/efeitos dos fármacos
Antagonistas Muscarínicos/toxicidade
Quinuclidinil Benzilato/toxicidade
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Aprendizagem da Esquiva/efeitos dos fármacos
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Atividade Motora/efeitos dos fármacos
Antagonistas Muscarínicos/química
Quinuclidinil Benzilato/química
Ratos
Ratos Wistar
Estatísticas não Paramétricas
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Muscarinic Antagonists); 6581-06-2 (Quinuclidinyl Benzilate)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:140415
[Lr] Data última revisão:
140415
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140318
[St] Status:MEDLINE


  8 / 2083 MEDLINE  
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[PMID]:24175711
[Au] Autor:Alfonzo MJ; De Alfonzo RG; Alfonzo-González MA; De Becemberg IL
[Ad] Endereço:Sección de Biomembranas, Instituto de Medicina Experimental (IME), Facultad de Medicina, Universidad Central de Venezuela (UCV) , Caracas , Venezuela.
[Ti] Título:Cyclic GMP regulates M3AChR activity at plasma membranes from airway smooth muscle.
[So] Source:Mol Membr Biol;30(8):403-17, 2013 Dec.
[Is] ISSN:1464-5203
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Muscarinic acetylcholine receptors MAChRs from Bovine Tracheal Smooth Muscle (BTSM) plasma membranes are responsible for the cGMP rise and signal-amplitude peaks associated with smooth muscle contraction present in bronchial asthma. These MAChRs bind [(3)H]QNB and exhibit the classic G Protein Coupled-Receptor (GPCR) behavior towards muscarinic agonist and antagonists that is sensitive to sensitive to GTP analogs. Interestingly, the [(3)H]QNB binding activity was stimulated by cGMP and ATP, and was enhanced by IBMX and Zaprinast, inhibitors of cGMP-PDE. Cyclic GMP plus ATP affected the agonist-antagonist muscarinic binding activities. Thus, the high affinity agonist (Carbamylcholine) binding sites disappeared, whereas, 4-DAMP, a M3 selective antagonist displayed an additional high affinity-binding site. In contrast, non-selective (atropine) and M2-selective (methoctramine and gallamine) antagonists revealed one low binding site. Moreover, the 4-DAMP-mustard alkylation of the MAChRs blocked the cGMP effect indicating that the M3AChR is the main receptor target of cGMP. Interestingly, these cGMP effects were potentiated by an activator (Sp-8-pCPT-cGMPS), and diminished by an inhibitor (Rp-8-pCPT-CGMPS), of cGMP-dependent protein kinase (PKG-II), which was detected by Western blotting using specific PKG II antibodies. Finally, plasma membrane M3AChRs were phosphorylated in a cGMP-dependent manner and this novel post-translational reversible modification at M3AChRs may act as a feedback mechanism to terminate the cGMP dependent muscarinic signal transduction cascades at the sarcolema of BTSM.
[Mh] Termos MeSH primário: GMP Cíclico/metabolismo
Músculo Liso/metabolismo
Receptores Muscarínicos/metabolismo
Transdução de Sinais
Traqueia/metabolismo
[Mh] Termos MeSH secundário: Animais
Bovinos
Membrana Celular/metabolismo
Membrana Celular/ultraestrutura
Proteína Quinase Dependente de GMP Cíclico Tipo II/imunologia
Retroalimentação Fisiológica
Agonistas Muscarínicos/metabolismo
Antagonistas Muscarínicos/metabolismo
Piperidinas/metabolismo
Processamento de Proteína Pós-Traducional
Quinuclidinil Benzilato/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Piperidines); 0 (Receptors, Muscarinic); 6581-06-2 (Quinuclidinyl Benzilate); 81405-11-0 (4-diphenylacetoxy-1,1-dimethylpiperidinium); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type II); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1403
[Cu] Atualização por classe:131122
[Lr] Data última revisão:
131122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131102
[St] Status:MEDLINE
[do] DOI:10.3109/09687688.2013.851419


  9 / 2083 MEDLINE  
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[PMID]:23727356
[Au] Autor:Morishima S; Anisuzzaman AS; Uwada J; Yoshiki H; Muramatsu I
[Ad] Endereço:Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Eiheiji, Fukui 910-1193, Japan.
[Ti] Título:Comparison of subcellular distribution and functions between exogenous and endogenous M1 muscarinic acetylcholine receptors.
[So] Source:Life Sci;93(1):17-23, 2013 Jul 19.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Recombinant systems have been used for evaluating the properties of G-protein-coupled receptors (GPCRs) on the assumption of cell surface expression. However, many GPCRs, including muscarinic acetylcholine receptors (mAChRs), have also been reported to be distributed in intracellular organelles in native tissues and cell lines. In this study, we compared the pharmacological profiles of exogenously and endogenously expressed M1-mAChRs, and evaluated the functional properties of these receptors. MAIN METHODS: Recombinant M1-mAChRs were expressed exogenously in Chinese hamster ovary cells (CHO-M1 cells) and compared with endogenously expressed M1-mAChRs in N1E-115 neuroblastoma cells. The pharmacological and functional profiles were evaluated using cell-permeable antagonists (1-quinuclidinyl-benzilate (QNB), pirenzepine and atropine) and cell-impermeable antagonists (N-methylscopolamine (NMS) or MT-7). KEY FINDINGS: M1-mAChRs were seen at the cell surface and intracellular sites in both cell lines. Under whole cell conditions, intracellular M1-mAChRs were mainly recognized by cell-permeable ligands, but scarcely by cell-impermeable ligands (at less than 100nM). In CHO-M1 cells, M1-mAChR activation by carbachol resulted in Ca(2+) mobilization, ERK1/2 phosphorylation and a reduction in thymidine incorporation, all of which were completely inhibited by MT-7, indicating the involvement of surface M1-mAChRs. In N1E-115 cells, Ca(2+) mobilization occurred through surface M1-mAChRs, whereas ERK1/2 phosphorylation and acceleration of thymidine incorporation were mediated through intracellular M1-mAChRs. SIGNIFICANCE: Exogenous and endogenous M1-mAChRs are present at both the cell surface and the intracellular organelles, and the pharmacological properties of geographically distinct M1-mAChRs are different, and may depend on cell background and/or exogenous or endogenous origin.
[Mh] Termos MeSH primário: Organelas/metabolismo
Receptor Muscarínico M1/antagonistas & inibidores
Receptor Muscarínico M1/metabolismo
Proteínas Recombinantes/metabolismo
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Atropina
Western Blotting
Células CHO
Cálcio/metabolismo
Cricetinae
Cricetulus
Camundongos
Microscopia Confocal
N-Metilescopolamina
Pirenzepina
Quinuclidinil Benzilato
Ensaio Radioligante
Trítio
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptor, Muscarinic M1); 0 (Recombinant Proteins); 10028-17-8 (Tritium); 3G0285N20N (Pirenzepine); 6581-06-2 (Quinuclidinyl Benzilate); 7C0697DR9I (Atropine); SY7Q814VUP (Calcium); VDR09VTQ8U (N-Methylscopolamine)
[Em] Mês de entrada:1308
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130604
[St] Status:MEDLINE


  10 / 2083 MEDLINE  
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[PMID]:23389940
[Au] Autor:Johansson J; Landgren M; Fernell E; Lewander T; Venizelos N
[Ad] Endereço:Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, 701 82 Örebro, Sweden.
[Ti] Título:Decreased binding capacity (Bmax) of muscarinic acetylcholine receptors in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD).
[So] Source:Atten Defic Hyperact Disord;5(3):267-71, 2013 Sep.
[Is] ISSN:1866-6647
[Cp] País de publicação:Austria
[La] Idioma:eng
[Ab] Resumo:Monoaminergic dysregulation is implicated in attention-deficit/hyperactivity disorder (ADHD), and methylphenidate and amphetamines are the most frequently prescribed pharmacological agents for treating ADHD. However, it has recently been proposed that the core symptoms of the disorder might be due to an imbalance between monoaminergic and cholinergic systems. In this study, we used fibroblast cell homogenates from boys with and without ADHD as an extraneural cell model to examine the cholinergic receptor density, that is, muscarinic acetylcholine receptors (mAChRs). We found that the binding capacity (Bmax) of [³H] Quinuclidinyl benzilate (³H-QNB) to mAChRs was decreased by almost 50 % in the children with ADHD (mean = 30.6 fmol/mg protein, SD = 25.6) in comparison with controls [mean = 63.1 fmol/mg protein, SD = 20.5, p ≤ 0.01 (Student's unpaired t test)]. The decreased Bmax indicates a reduced cholinergic receptor density, which might constitute a biomarker for ADHD. However, these preliminary findings need to be replicated in larger ADHD and comparison cohorts.
[Mh] Termos MeSH primário: Transtorno do Deficit de Atenção com Hiperatividade/metabolismo
Fibroblastos/metabolismo
Receptores Muscarínicos/metabolismo
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Células Cultivadas
Criança
Seres Humanos
Masculino
Antagonistas Muscarínicos/análise
Antagonistas Muscarínicos/metabolismo
Quinuclidinil Benzilato/análise
Quinuclidinil Benzilato/metabolismo
Ensaio Radioligante
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Muscarinic Antagonists); 0 (Receptors, Muscarinic); 10028-17-8 (Tritium); 6581-06-2 (Quinuclidinyl Benzilate)
[Em] Mês de entrada:1410
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130208
[St] Status:MEDLINE
[do] DOI:10.1007/s12402-013-0103-0



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