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[PMID]:18322151
[Au] Autor:Avlani VA; McLoughlin DJ; Sexton PM; Christopoulos A
[Ad] Endereço:Drug Discovery Biology Laboratory, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
[Ti] Título:The impact of orthosteric radioligand depletion on the quantification of allosteric modulator interactions.
[So] Source:J Pharmacol Exp Ther;325(3):927-34, 2008 Jun.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Radioligand binding assays remain a common method for quantifying the effects of allosteric modulators at G protein-coupled receptors. The allosteric ternary complex model (ATCM) is the simplest model applied to derive estimates of modulator affinity (K(B)) and cooperativity (alpha), which are necessary for understanding structure-activity relationships. However, the increasing drive toward assay miniaturization in modern drug discovery may lead to conditions where appreciable ligand depletion occurs in the assay. Theoretical simulations investigating the impact of orthosteric radioligand depletion on the estimation of ATCM parameters revealed the following. 1) For allosteric inhibitors, application of the standard ATCM to data obtained under depletion conditions leads to an underestimation of pK(B) and an overestimation of log alpha. 2) For allosteric enhancers, the opposite was noted, but not always; the nonlinear regression algorithm is more likely to struggle to converge to a satisfactory solution of (nondepletion) ATCM parameters in this situation. 3) Application of a novel ATCM that explicitly incorporates orthosteric ligand depletion will yield more reliable model estimates, provided the degree of depletion is not high (< approximately 50%). Subsequent experiments investigated the interaction between [3H]N-methylscopolamine and the allosteric enhancer, alcuronium, or inhibitor, gallamine, in the presence of increasing concentrations of M(2) muscarinic acetylcholine receptor and showed that application of an ATCM that explicitly incorporates radioligand depletion can indeed give more robust estimates of modulator affinity and cooperativity estimates than the standard model. These results have important implications for the quantification of allosteric modulator actions in binding-based discovery assays.
[Mh] Termos MeSH primário: Regulação Alostérica
Modelos Biológicos
Receptor Muscarínico M2/metabolismo
[Mh] Termos MeSH secundário: Alcurônio/metabolismo
Animais
Atropina/metabolismo
Células CHO
Carbacol/metabolismo
Membrana Celular/metabolismo
Cricetinae
Cricetulus
Trietiodeto de Galamina/metabolismo
Ligantes
N-Metilescopolamina/metabolismo
Ensaio Radioligante
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (Receptor, Muscarinic M2); 10028-17-8 (Tritium); 7C0697DR9I (Atropine); 8Y164V895Y (Carbachol); Q3254X40X2 (Gallamine Triethiodide); S8U3J5W06N (Alcuronium); VDR09VTQ8U (N-Methylscopolamine)
[Em] Mês de entrada:0806
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:080307
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.108.136978


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[PMID]:15333678
[Au] Autor:May LT; Lin Y; Sexton PM; Christopoulos A
[Ad] Endereço:Department of Pharmacology, University of Melbourne, Grattan St., Parkville, 3010, Victoria, Australia.
[Ti] Título:Regulation of M2 muscarinic acetylcholine receptor expression and signaling by prolonged exposure to allosteric modulators.
[So] Source:J Pharmacol Exp Ther;312(1):382-90, 2005 Jan.
[Is] ISSN:0022-3565
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The effects of prolonged exposure of M(2) muscarinic acetylcholine receptors (mAChRs), stably expressed in Chinese hamster ovary cells, to the allosteric modulators gallamine, alcuronium, and heptane-1,7-bis (dimethyl-3'-phthalimidopropyl)-ammonium bromide (C(7)/3'-phth) were compared with the effects of the agonist carbachol (CCh) and antagonists atropine and N-methylscopolamine (NMS). Intact cell saturation binding assays using [(3)H]NMS found that pretreatment of the cells for 24 h with CCh caused a significant down-regulation of receptor number, whereas atropine, NMS, and all three allosteric modulators caused receptor up-regulation. Functional assays using a cytosensor microphysiometer to measure whole-cell metabolic rate found no acute effects of gallamine on receptor signaling, whereas atropine seemed to behave as an inverse agonist. Pretreatment of the cells with gallamine (20 microM) or atropine (20 nM) resulted in a significant enhancement of the maximal effect evoked by CCh. In contrast, CCh (100 microM) pretreatment resulted in a significant reduction in maximal receptor signaling capacity. Time-course experiments revealed that the effects of atropine and gallamine on receptor up-regulation are only visualized after at least 12-h ligand exposure, compared with the more rapid effects of CCh, which achieve steady-state down-regulation within 90 min. Additional experiments monitoring CCh-mediated M(2) mAChR internalization in the presence of gallamine revealed that part of the mechanism underlying the effects of the modulator on receptor expression may involve a change in receptor internalization properties. These findings suggest that, like orthosteric ligands, G protein-coupled receptor allosteric modulators also are able to mediate long-term effects on receptor regulation.
[Mh] Termos MeSH primário: Regulação Alostérica
Antagonistas Nicotínicos/farmacologia
Receptor Muscarínico M2/metabolismo
[Mh] Termos MeSH secundário: Alcurônio/farmacologia
Animais
Células CHO
Cricetinae
Feminino
Trietiodeto de Galamina/farmacologia
Expressão Gênica/efeitos dos fármacos
Ligantes
Ftalimidas/farmacologia
Compostos de Amônio Quaternário/farmacologia
Receptor Muscarínico M2/efeitos dos fármacos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (Nicotinic Antagonists); 0 (Phthalimides); 0 (Quaternary Ammonium Compounds); 0 (Receptor, Muscarinic M2); 0 (heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl)ammonium bromide); Q3254X40X2 (Gallamine Triethiodide); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0504
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:040831
[St] Status:MEDLINE


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[PMID]:15494038
[Au] Autor:Christopoulos A; May LT; Avlani VA; Sexton PM
[Ad] Endereço:Department of Pharmacology, University of Melbourne, Grattan St., Parkville, 3010, Victoria, Australia.
[Ti] Título:G-protein-coupled receptor allosterism: the promise and the problem(s).
[So] Source:Biochem Soc Trans;32(Pt 5):873-7, 2004 Nov.
[Is] ISSN:0300-5127
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more 'physiological' regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.
[Mh] Termos MeSH primário: Desenho de Drogas
Receptores Acoplados a Proteínas-G/química
[Mh] Termos MeSH secundário: Alcurônio/farmacologia
Sítio Alostérico
Animais
Sítios de Ligação
Relação Dose-Resposta a Droga
Seres Humanos
Cinética
Ligantes
Modelos Químicos
Ligação Proteica
Estrutura Terciária de Proteína
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, G-Protein-Coupled); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0504
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:041021
[St] Status:MEDLINE


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[PMID]:15204035
[Au] Autor:Kenakin T
[Ad] Endereço:Molecular Discovery, GlaxoSmithKline Research and Development, 5 Moore Drive, RTP 27709, USA. terry.p.kenakin@gsk.com
[Ti] Título:G-protein coupled receptors as allosteric machines.
[So] Source:Receptors Channels;10(2):51-60, 2004.
[Is] ISSN:1060-6823
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Allosterism, whereby small molecule ligands produce global changes in the conformations of receptors, is a powerful mechanism for drug effect. This is illustrated by the recent data describing CCR5 antagonists as blockers of HIV infection. Allosteric effects are described in terms of a change in the tertiary conformation of the receptor. This paper outlines some unique features of allosteric antagonists as new drug entities. These include the fact that allosteric ligands have texture in antagonism (not all allosterically blocked receptors are alike), allosteric blockade is probe dependent (not all agonists and radioligands are blocked equally), and the fact that allosteric binding involves a separate site on the receptor may have relevance to duration of effect and selectivity. Dissociation between receptor function and binding also can be encountered with allosteric ligands.
[Mh] Termos MeSH primário: Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Alcurônio/farmacologia
Regulação Alostérica
Sítio Alostérico
Fármacos Anti-HIV/farmacologia
Antagonistas dos Receptores CCR5
Trietiodeto de Galamina/farmacologia
Infecções por HIV/tratamento farmacológico
Infecções por HIV/prevenção & controle
Seres Humanos
Ligantes
Modelos Moleculares
Receptor Muscarínico M2/antagonistas & inibidores
Receptor Muscarínico M2/química
Receptor Muscarínico M2/metabolismo
Receptores CXCR4/antagonistas & inibidores
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Receptores Acoplados a Proteínas-G/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (CCR5 Receptor Antagonists); 0 (Ligands); 0 (Receptor, Muscarinic M2); 0 (Receptors, CXCR4); 0 (Receptors, G-Protein-Coupled); Q3254X40X2 (Gallamine Triethiodide); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0501
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:040619
[St] Status:MEDLINE


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[PMID]:12893536
[Au] Autor:Mohr K; Tränkle C; Holzgrabe U
[Ad] Endereço:Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany. k.mohr@uni-bonn.de
[Ti] Título:Structure/activity relationships of M2 muscarinic allosteric modulators.
[So] Source:Receptors Channels;9(4):229-40, 2003.
[Is] ISSN:1060-6823
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Allosteric modulation of G protein-coupled receptors has been intensively studied at muscarinic acetylcholine receptors. Findings made with archetypal allosteric agents such as gallamine, alcuronium, and bis(ammonio)alkane-type agents revealed that binding of orthosteric ligands that attach to the acetylcholine site can be allosterically decreased or increased or left unaltered in a subtype-selective fashion. Analyses of structure/activity relationships (SARs) help to elucidate the molecular events underlying the allosteric action and they may pilot the development of new allosteric agents with improved properties and therapeutic perspectives. With a focus on SARs, this review illustrates the principles of muscarinic allosteric interactions, gives an overview of SARs in congeners of archetypal allosteric agents, and considers the topology of M(2) muscarinic allosteric interactions that are characterized by divergent binding modes.
[Mh] Termos MeSH primário: Receptor Muscarínico M2/química
Receptor Muscarínico M2/metabolismo
[Mh] Termos MeSH secundário: Alcurônio/análogos & derivados
Alcurônio/metabolismo
Alcanos/metabolismo
Regulação Alostérica
Animais
Seres Humanos
Receptor Muscarínico M2/antagonistas & inibidores
Transdução de Sinais/fisiologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Alkanes); 0 (Receptor, Muscarinic M2); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0404
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:030802
[St] Status:MEDLINE


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[PMID]:12873942
[Au] Autor:Messner M; Beese U; Romstöck J; Dinkel M; Tschaikowsky K
[Ad] Endereço:Department of Anesthesiology, Friedrich-Alexander Universität, Erlangen-Nuernberg, Germany. messner@gmx.li
[Ti] Título:The bispectral index declines during neuromuscular block in fully awake persons.
[So] Source:Anesth Analg;97(2):488-91, table of contents, 2003 Aug.
[Is] ISSN:0003-2999
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Bispectral index (BIS) is an electroencephalographic variable promoted for measuring depth of anesthesia. Electromyographic activity influences surface electroencephalography and the calculation of BIS. In this study, we sought to determine the effect of spontaneous electromyographic activity on BIS. BIS was monitored in three volunteers by using an Aspect A-1000 monitor. The experiment was repeated in one volunteer. Electromyographic activity was recorded. Alcuronium and succinylcholine were administered. No other drugs were used. In parallel with spontaneous electromyographic activity of the facial muscles, BIS decreased in response to muscle relaxation to a minimum value of 33 and, in the repeated measurement, to a minimum value of 9 when total neuromuscular block was achieved. In two volunteers, no total block was achieved. BIS decreased to a minimal value of 64 and 57, respectively. In turn, recovery of BIS coincided with the reappearance of spontaneous electromyographic activity. During the entire experiment, the volunteers had full consciousness. BIS, assessed by software Version 3.31, correlates with spontaneous electromyographic activity of the facial muscles. BIS failed to detect awareness in completely paralyzed subjects. Thus, in paralyzed patients, BIS monitoring may not reliably indicate a decline in sedation and imminent awareness. IMPLICATIONS: The bispectral index (BIS) is an electroencephalographic variable intended for measuring depth of anesthesia. Electromyographic activity influences the calculation of BIS. We found that the administration of a muscle relaxant to unanesthetized volunteers decreases the bispectral index value. Thus, awareness in totally paralyzed patients cannot be excluded.
[Mh] Termos MeSH primário: Estado de Consciência/fisiologia
Eletroencefalografia/efeitos dos fármacos
Eletromiografia
Bloqueio Neuromuscular
[Mh] Termos MeSH secundário: Alcurônio
Músculos Faciais/fisiologia
Seres Humanos
Relaxamento Muscular
Fármacos Neuromusculares Despolarizantes
Fármacos Neuromusculares não Despolarizantes
Succinilcolina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neuromuscular Depolarizing Agents); 0 (Neuromuscular Nondepolarizing Agents); J2R869A8YF (Succinylcholine); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0308
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:030723
[St] Status:MEDLINE


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[PMID]:12835873
[Au] Autor:Hofmockel R; Geldner G; Diefenbach C; Fuchs-Buder T; Ulm K; Blobner M
[Ad] Endereço:Klinik für Anästhesiologie und Intensivtherapie, Universität Rostock. rainer.hofmockel@med.uni-rostock.de
[Ti] Título:[Application of muscle relaxants for rapid-sequence induction of anaesthesia].
[Ti] Título:Die Anwendung von Muskelrelaxanzien zur Blitzintubation in Deutschland..
[So] Source:Anaesthesist;52(6):516-21, 2003 Jun.
[Is] ISSN:0003-2417
[Cp] País de publicação:Germany
[La] Idioma:ger
[Ab] Resumo:The present study evaluates the use of muscle relaxants for rapid-sequence induction (RSI) and different application techniques (pre-curarisation, priming, timing) as a part of a nationwide survey in Germany. In 86.8% of anaesthesia departments succinylcholine is used for RSI and an average of 56.5% of respondents used only succinylcholine for RSI. Of all non-depolarising muscle relaxants rocuronium is the most frequently used alternative. Of the anaesthesia departments 2.6% use rocuronium regularly in patients with increased risk for aspiration of stomach contents; level one centres significantly more than others, 12.9% answered that pre-curarisation techniques were never used, whereas 45.6% use non-depolarising neuromuscular blocking drugs before giving succinylcholine in 80-100% of cases. Priming is not used by 64.4% of respondents, as opposed to 9.8% who utilise this technique regularly. The statements regarding timing are 71.1% and 5.4%, respectively. Alcuronium is used for RSI in departments in which the financial aspect is the primary decision criteria. Despite ist known side-effects and the on-going discussion over the past years, succinylcholine is still the most frequently used muscle relaxants for RSI. Priming is often declined by anaesthetists in Germany, most probably due to the absence of clear advantages and the possibility of severe complications. It is the opinion of the authors that timing but also drugs with a slow onset (e.g., alcuronium and Pancuronium) are obsolete in the context of RSI.
[Mh] Termos MeSH primário: Anestesia
Relaxantes Musculares Centrais
[Mh] Termos MeSH secundário: Alcurônio
Androstanóis
Coleta de Dados
Uso de Medicamentos
Alemanha
Seres Humanos
Fármacos Neuromusculares Despolarizantes
Fármacos Neuromusculares não Despolarizantes
Pneumonia Aspirativa/prevenção & controle
Risco
Succinilcolina
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstanols); 0 (Muscle Relaxants, Central); 0 (Neuromuscular Depolarizing Agents); 0 (Neuromuscular Nondepolarizing Agents); J2R869A8YF (Succinylcholine); S8U3J5W06N (Alcuronium); WRE554RFEZ (rocuronium)
[Em] Mês de entrada:0308
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:030702
[St] Status:MEDLINE


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[PMID]:12039641
[Au] Autor:Wedig M; Novatchev N; Worch T; Laug S; Holzgrabe U
[Ad] Endereço:Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
[Ti] Título:Evaluation of the impurity profile of alcuronium by means of capillary electrophoresis.
[So] Source:J Pharm Biomed Anal;28(5):983-90, 2002 Jun 01.
[Is] ISSN:0731-7085
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Alcuronium, a neuromuscular blocking drug, was recently introduced to the European Pharmacopoeia. A HPLC method is described to limit the impurities of alcuronium, namely the diallylcaracurine (DAC) and the allyl-Wieland-Gumlich-aldehyde (WCA), to less than 0.5%. Since alcuronium and all impurities are quaternary salts, capillary electrophoresis (CE) is highly suitable to evaluate the impurity profile. Using 12 mM heptakis-(2,6-di-O-methyl)-beta-cyclodextrin in a 50 mM phosphate buffer at pH 5.5 or 50 mM diethanolamine buffer (pH 9.2)-acetonitrile 19:1 containing heptakis-(2,3-O-diacetyl-6-sulfo)-beta-cyclodextrin the impurities could be baseline separated and quantified. The limit of detection for DAC and WCA was found to be in the same range as found with HPLC; thus, less than 0.1% of both DAC and WCA could be detected in the solution for injection in presence of alcuronium. In injection solutions of alcuronium which were stored at higher temperatures three additional, unidentified impurities were detected. In addition, the conversion of alcuronium to DAC, occurring under acidic condition, was monitored by means of the CE method developed.
[Mh] Termos MeSH primário: Alcurônio/análise
Fármacos Neuromusculares não Despolarizantes/análise
[Mh] Termos MeSH secundário: Ciclização
Contaminação de Medicamentos
Estabilidade de Medicamentos
Armazenamento de Medicamentos
Eletroforese Capilar
Concentração de Íons de Hidrogênio
Soluções
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Neuromuscular Nondepolarizing Agents); 0 (Solutions); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0208
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:020601
[St] Status:MEDLINE


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[PMID]:11961078
[Au] Autor:Zahn K; Eckstein N; Tränkle C; Sadée W; Mohr K
[Ad] Endereço:Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Germany.
[Ti] Título:Allosteric modulation of muscarinic receptor signaling: alcuronium-induced conversion of pilocarpine from an agonist into an antagonist.
[So] Source:J Pharmacol Exp Ther;301(2):720-8, 2002 May.
[Is] ISSN:0022-3565
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M(2) subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M(2)-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC(50, Alc) = 5.63) without any effect on the EC(50) of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pK(A, Alc) = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 microM alcuronium. Measuring guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in CHO-M(2) membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [(35)S]GTPgammaS binding (pIC(50, Alc) = 5.47) without shift in EC(50), whereas it competitively shifted the response to oxotremorine M (pK(A, Alc) = 5.97). [(3)H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist-a novel type of functional allosteric interaction.
[Mh] Termos MeSH primário: Alcurônio/farmacologia
Pilocarpina/farmacologia
Receptores Muscarínicos/metabolismo
Transdução de Sinais/fisiologia
Vasoconstrição/efeitos dos fármacos
[Mh] Termos MeSH secundário: Regulação Alostérica
Animais
Função Atrial
Células CHO
Cricetinae
Interações Medicamentosas
Proteínas de Ligação ao GTP/metabolismo
Átrios do Coração/efeitos dos fármacos
Agonistas Muscarínicos/farmacologia
Antagonistas Muscarínicos/farmacologia
Receptor Muscarínico M2
Receptores Muscarínicos/efeitos dos fármacos
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Receptor, Muscarinic M2); 0 (Receptors, Muscarinic); 01MI4Q9DI3 (Pilocarpine); EC 3.6.1.- (GTP-Binding Proteins); S8U3J5W06N (Alcuronium)
[Em] Mês de entrada:0205
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:020419
[St] Status:MEDLINE


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[PMID]:11562438
[Au] Autor:Krejcí A; Tucek S
[Ad] Endereço:Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
[Ti] Título:Changes of cooperativity between N-methylscopolamine and allosteric modulators alcuronium and gallamine induced by mutations of external loops of muscarinic M(3) receptors.
[So] Source:Mol Pharmacol;60(4):761-7, 2001 Oct.
[Is] ISSN:0026-895X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To clarify the involvement of specific domains of muscarinic receptors in the action of allosteric modulators, muscarinic M(3) receptors (on which allosteric interactions are weak) were genetically modified to become more similar to M(2) receptors (on which allosteric interactions are strong) and were expressed in COS-7 cells. Affinity for allosteric modulator gallamine was enhanced 25- to 50-fold by modifications of the third external loop (o3) and the negative effect of gallamine on the affinity for classical antagonist N-[(3)H]methylscopolamine ([(3)H]NMS) was augmented. Affinity for alcuronium became 3-fold higher after the o3 loop of M(3) receptors was made identical with the o3 loop of M(2) receptors, and alcuronium acquired positive influence on the affinity for [(3)H]NMS. This is the first instance of inducing positive cooperativity on muscarinic receptors by genetic manipulation. Transferring whole o2 loop from M(2) to M(3) receptors substantially enhanced affinities for gallamine and alcuronium without augmenting their negative action on [(3)H]NMS binding. In contrast, effects of simply adding two negative charges into the o2 loop of M(3) receptors were small. Removal of Arg from o1 loop abolished the negative effect of gallamine but not of alcuronium on [(3)H]NMS binding at equilibrium. Data point to an important role of o3 loop in the mechanism of the positive and negative cooperativity between [(3)H]NMS and alcuronium and gallamine, respectively, and in the binding of both modulators to M(2) receptors and reveal independence between mutation-induced changes in the affinity for a modulator and in the magnitude and direction of the allosteric effect of the modulator.
[Mh] Termos MeSH primário: Alcurônio/farmacologia
Trietiodeto de Galamina/farmacologia
N-Metilescopolamina/farmacologia
Receptores Muscarínicos/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Sequência de Aminoácidos
Arginina/genética
Sítios de Ligação
Glicina/genética
Seres Humanos
Dados de Sequência Molecular
Mutação
Antagonistas Nicotínicos/farmacologia
Parassimpatolíticos/farmacologia
Conformação Proteica
Ensaio Radioligante
Receptor Muscarínico M3
Receptores Muscarínicos/química
Receptores Muscarínicos/efeitos dos fármacos
Receptores Muscarínicos/genética
Homologia de Sequência de Aminoácidos
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nicotinic Antagonists); 0 (Parasympatholytics); 0 (Receptor, Muscarinic M3); 0 (Receptors, Muscarinic); 10028-17-8 (Tritium); 94ZLA3W45F (Arginine); Q3254X40X2 (Gallamine Triethiodide); S8U3J5W06N (Alcuronium); TE7660XO1C (Glycine); VDR09VTQ8U (N-Methylscopolamine)
[Em] Mês de entrada:0110
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:010920
[St] Status:MEDLINE



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