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Pesquisa : D03.633.100.079.080.070.750 [Categoria DeCS]
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  1 / 3708 MEDLINE  
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[PMID]:28558964
[Au] Autor:Rahman Y; Afrin S; Husain MA; Sarwar T; Ali A; Shamsuzzaman; Tabish M
[Ad] Endereço:Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, U.P. 202002, India.
[Ti] Título:Unravelling the interaction of pirenzepine, a gastrointestinal disorder drug, with calf thymus DNA: An in vitro and molecular modelling study.
[So] Source:Arch Biochem Biophys;625-626:1-12, 2017 Jul 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pirenzepine is an anti-ulcer agent which belongs to the anti-cholinergic group of gastrointestinal disorder drugs and functions as an M1 receptor selective antagonist. Drug-DNA interaction studies are of great significance as it helps in the development of new therapeutic drugs. It provides a deeper understanding into the mechanism through which therapeutic drugs control gene expression. Interaction of pirenzepine with calf-thymus DNA (Ct-DNA) was determined via a series of biophysical techniques. UV-visible absorption and fluorescence spectroscopy confirmed the formation of pirenzepine-Ct-DNA complex. The values of binding constant from various experiments were calculated to be in the order of 10 M which is consistent with the groove binding mode. Various spectrofluorimetric experiments like competitive displacement of well known dyes with drug, iodide quenching experiments and the effect of Ct-DNA denaturation in presence of drug confirmed the binding of pirenzepine to the groove of Ct-DNA. The binding mode was further established by viscometric, circular dichroic and molecular modelling studies. Thermodynamic parameters obtained from isothermal titration calorimetric studies suggest that the interaction of pirenzepine with Ct-DNA is enthalpically driven. The value of TΔS and ΔH calculated from calorimetric studies were found to be 4.3 kcal mol and -2.54 kcal mol respectively, indicating that pirenzepine-Ct-DNA complex is mainly stabilized by hydrophobic interaction and hydrogen bonding. The binding energy calculated was -7.5 kcal mol from modelling studies which was approximately similar to that obtained by isothermal titration calorimetric studies. Moreover, the role of electrostatic interaction in the binding of pirenzepine to Ct-DNA cannot be precluded.
[Mh] Termos MeSH primário: DNA/metabolismo
Fármacos Gastrointestinais/metabolismo
Pirenzepina/metabolismo
[Mh] Termos MeSH secundário: Animais
Calorimetria
Bovinos
DNA/química
Simulação de Acoplamento Molecular
Conformação de Ácido Nucleico/efeitos dos fármacos
Desnaturação de Ácido Nucleico/efeitos dos fármacos
Espectrometria de Fluorescência
Espectrofotometria Ultravioleta
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gastrointestinal Agents); 3G0285N20N (Pirenzepine); 9007-49-2 (DNA); 91080-16-9 (calf thymus DNA)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE


  2 / 3708 MEDLINE  
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[PMID]:28326934
[Au] Autor:Koga K; Matsuzaki Y; Honda K; Eto F; Furukawa T; Migita K; Irie K; Mishima K; Ueno S
[Ad] Endereço:1 Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Japan.
[Ti] Título:Activations of muscarinic M receptors in the anterior cingulate cortex contribute to the antinociceptive effect via GABAergic transmission.
[So] Source:Mol Pain;13:1744806917692330, 2017 Jan.
[Is] ISSN:1744-8069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background Cholinergic systems regulate the synaptic transmission resulting in the contribution of the nociceptive behaviors. Anterior cingulate cortex is a key cortical area to play roles in nociception and chronic pain. However, the effect of the activation of cholinergic system for nociception is still unknown in the cortical area. Here, we tested whether the activation of cholinergic receptors can regulate nociceptive behaviors in adult rat anterior cingulate cortex by integrative methods including behavior, immunohistochemical, and electrophysiological methods. Results We found that muscarinic M receptors were clearly expressed in the anterior cingulate cortex. Using behavioral tests, we identified that microinjection of a selective muscarinic M receptors agonist McN-A-343 into the anterior cingulate cortex dose dependently increased the mechanical threshold. In contrast, the local injection of McN-A-343 into the anterior cingulate cortex showed normal motor function. The microinjection of a selective M receptors antagonist pirenzepine blocked the McN-A-343-induced antinociceptive effect. Pirenzepine alone into the anterior cingulate cortex decreased the mechanical thresholds. The local injection of the GABA receptors antagonist bicuculline into the anterior cingulate cortex also inhibited the McN-A-343-induced antinociceptive effect and decreased the mechanical threshold. Finally, we further tested whether the activation of M receptors could regulate GABAergic transmission using whole-cell patch-clamp recordings. The activation of M receptors enhanced the frequency of spontaneous and miniature inhibitory postsynaptic currents as well as the amplitude of spontaneous inhibitory postsynaptic currents in the anterior cingulate cortex. Conclusions These results suggest that the activation of muscarinic M receptors in part increased the mechanical threshold by increasing GABAergic transmitter release and facilitating GABAergic transmission in the anterior cingulate cortex.
[Mh] Termos MeSH primário: Analgésicos/uso terapêutico
Giro do Cíngulo/metabolismo
Hiperalgesia/tratamento farmacológico
Receptor Muscarínico M1/metabolismo
Transmissão Sináptica/fisiologia
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia
Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/uso terapêutico
Analgésicos/farmacologia
Animais
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Fármacos atuantes sobre Aminoácidos Excitatórios/farmacologia
GABAérgicos/farmacologia
Giro do Cíngulo/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/fisiologia
Masculino
Atividade Motora/efeitos dos fármacos
Atividade Motora/fisiologia
Agonistas Muscarínicos/farmacologia
Agonistas Muscarínicos/uso terapêutico
Antagonistas Muscarínicos/farmacologia
Pirenzepina/farmacologia
Ratos
Ratos Wistar
Transmissão Sináptica/efeitos dos fármacos
Ácido gama-Aminobutírico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Excitatory Amino Acid Agents); 0 (GABA Agents); 0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Receptor, Muscarinic M1); 3G0285N20N (Pirenzepine); 55-45-8 ((4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1177/1744806917692330


  3 / 3708 MEDLINE  
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[PMID]:28223240
[Au] Autor:Lévesque M; Cataldi M; Chen LY; Hamidi S; Avoli M
[Ad] Endereço:Montreal Neurological Institute and Department of Neurology & Neurosurgery, McGill University, 3801 University Street, Montréal, PQ H3A 2B4, Canada.
[Ti] Título:Carbachol-induced network oscillations in an in vitro limbic system brain slice.
[So] Source:Neuroscience;348:153-164, 2017 Apr 21.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We employed simultaneous field potential recordings from CA3, subiculum and entorhinal cortex in an in vitro brain slice preparation to understand the involvement of these limbic areas in the generation of the field potential oscillations that are induced by bath application of the muscarinic receptor agonist carbachol. Regularly spaced oscillations that mainly presented at theta frequency range (5-12Hz) occurred synchronously in all three structures in the presence of carbachol. These oscillations, which disappeared when slices were perfused with pirenzepine or with glutamatergic receptor antagonists, were categorized as short (<4s) and long (>4s) with short events oscillating at higher frequencies than long events. Field oscillations were highly synchronized between regions and latency analysis revealed that they often initiated in the entorhinal cortex later than in the other two structures. Blocking GABA receptors modified the activity patterns of both short and long oscillations and decreased their coherence in the theta frequency range. Finally, blocking KCC2 activity disclosed a pattern of recurrent short oscillations. Our results suggest that in the presence of carbachol both subiculum and CA3 most often drive theta generators in the entorhinal cortex and that these oscillations are influenced but not abolished by altering GABA receptor signaling.
[Mh] Termos MeSH primário: Região CA3 Hipocampal/efeitos dos fármacos
Carbacol/farmacologia
Agonistas Colinérgicos/farmacologia
Córtex Entorrinal/efeitos dos fármacos
Hipocampo/efeitos dos fármacos
Rede Nervosa/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Masculino
Antagonistas Muscarínicos/farmacologia
Neurônios/efeitos dos fármacos
Pirenzepina/farmacologia
Ratos
Ratos Sprague-Dawley
Ritmo Teta/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinergic Agonists); 0 (Muscarinic Antagonists); 3G0285N20N (Pirenzepine); 8Y164V895Y (Carbachol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170223
[St] Status:MEDLINE


  4 / 3708 MEDLINE  
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[PMID]:27606721
[Au] Autor:Mannan Baig A; Khan NA; Effendi V; Rana Z; Ahmad HR; Abbas F
[Ad] Endereço:aDepartment of Biological and Biomedical Sciences, Aga Khan University bDepartment of Surgery, Aga Khan University Hospital, Karachi, Pakistan cDepartment of Biological Sciences, Faculty of Science and Technology, Sunway University, Subang Jaya, Malaysia.
[Ti] Título:Differential receptor dependencies: expression and significance of muscarinic M1 receptors in the biology of prostate cancer.
[So] Source:Anticancer Drugs;28(1):75-87, 2017 Jan.
[Is] ISSN:1473-5741
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 µg/ml of dicyclomine. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer.
[Mh] Termos MeSH primário: Neoplasias da Próstata/metabolismo
Receptor Muscarínico M1/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/fisiologia
Diciclomina/farmacologia
Seres Humanos
Masculino
Pirenzepina/farmacologia
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/genética
Neoplasias da Próstata/patologia
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptor Muscarínico M1/antagonistas & inibidores
Receptor Muscarínico M1/biossíntese
Receptor Muscarínico M1/genética
Receptor Muscarínico M3/biossíntese
Receptor Muscarínico M3/genética
Receptor Muscarínico M3/metabolismo
Receptores Androgênicos/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, human); 0 (CHRM1 protein, human); 0 (CHRM3 protein, human); 0 (Receptor, Muscarinic M1); 0 (Receptor, Muscarinic M3); 0 (Receptors, Androgen); 3G0285N20N (Pirenzepine); 4KV4X8IF6V (Dicyclomine); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160909
[St] Status:MEDLINE


  5 / 3708 MEDLINE  
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[PMID]:27080256
[Au] Autor:Pediani JD; Ward RJ; Godin AG; Marsango S; Milligan G
[Ad] Endereço:From the Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom and.
[Ti] Título:Dynamic Regulation of Quaternary Organization of the M1 Muscarinic Receptor by Subtype-selective Antagonist Drugs.
[So] Source:J Biol Chem;291(25):13132-46, 2016 Jun 17.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although rhodopsin-like G protein-coupled receptors can exist as both monomers and non-covalently associated dimers/oligomers, the steady-state proportion of each form and whether this is regulated by receptor ligands are unknown. Herein we address these topics for the M1 muscarinic acetylcholine receptor, a key molecular target for novel cognition enhancers, by using spatial intensity distribution analysis. This method can measure fluorescent particle concentration and assess oligomerization states of proteins within defined regions of living cells. Imaging and analysis of the basolateral surface of cells expressing some 50 molecules·µm(-2) human muscarinic M1 receptor identified a ∼75:25 mixture of receptor monomers and dimers/oligomers. Both sustained and shorter term treatment with the selective M1 antagonist pirenzepine resulted in a large shift in the distribution of receptor species to favor the dimeric/oligomeric state. Although sustained treatment with pirenzepine also resulted in marked up-regulation of the receptor, simple mass action effects were not the basis for ligand-induced stabilization of receptor dimers/oligomers. The related antagonist telenzepine also produced stabilization and enrichment of the M1 receptor dimer population, but the receptor subtype non-selective antagonists atropine and N-methylscopolamine did not. In contrast, neither pirenzepine nor telenzepine altered the quaternary organization of the related M3 muscarinic receptor. These data provide unique insights into the selective capacity of receptor ligands to promote and/or stabilize receptor dimers/oligomers and demonstrate that the dynamics of ligand regulation of the quaternary organization of G protein-coupled receptors is markedly more complex than previously appreciated. This may have major implications for receptor function and behavior.
[Mh] Termos MeSH primário: Atropina/farmacologia
Antagonistas Muscarínicos/farmacologia
Pirenzepina/análogos & derivados
Pirenzepina/farmacologia
Multimerização Proteica/efeitos dos fármacos
Receptor Muscarínico M1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Receptor Muscarínico M1/química
Receptor Muscarínico M1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Muscarinic Antagonists); 0 (Receptor, Muscarinic M1); 0990EG3K10 (telenzepine); 3G0285N20N (Pirenzepine); 7C0697DR9I (Atropine)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160416
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.712562


  6 / 3708 MEDLINE  
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[PMID]:26849777
[Au] Autor:Lu ML; Wu YX; Chen CH; Kuo PT; Chen YH; Lin CH; Wu TH
[Ad] Endereço:Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
[Ti] Título:Application of Plasma Levels of Olanzapine and N-Desmethyl-Olanzapine to Monitor Clinical Efficacy in Patients with Schizophrenia.
[So] Source:PLoS One;11(2):e0148539, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: This therapeutic drug monitoring (TDM) study aimed to determine the role of olanzapine (OLZ) and N-desmethyl-OLZ (DMO) levels in the therapeutic efficacy of OLZ in patients with schizophrenia. METHOD: Plasma concentrations of OLZ (COLZ) and DMO (CDMO) in schizophrenic patients 12 hours post-dose were assessed. The correlations of COLZ and CDMO with the various scores of the Positive and Negative Syndrome Scale (PANSS) were evaluated. A receiver operating characteristic curve (ROC) was utilized to identify the threshold COLZ and COLZ/CDMO ratio for maintenance of satisfactory efficacy. RESULTS: A total of 151 samples from patients with schizophrenia were analyzed for individual COLZ and CDMO levels. The mean COLZ and CDMO levels were 37.0 ± 25.6 and 6.9 ± 4.7 ng/mL, respectively, and COLZ was ~50% higher in female or nonsmokers (p<0.01). In all patients, the daily dose of OLZ was positively correlated with COLZ and CDMO. Linear relationships between COLZ and OLZ dose were observed in both nonsmokers and smokers (rs = 0.306, 0.426, p<0.01), although CDMO was only correlated with OLZ dose in smokers (rs = 0.485, p<0.01) and not nonsmokers. In all patients, COLZ was marginally negatively correlated with the total PANSS score. The total PANSS score was significantly negatively correlated with the COLZ/CDMO ratio (p<0.005), except in smokers. The ROC analysis identified a COLZ/CDMO ratio ≥2.99 or COLZ ≥22.77 ng/mL as a predictor of maintenance of an at least mildly ill status (PANSS score ≤58) of schizophrenia in all patients. CONCLUSIONS: A significantly negative correlation between the steady-state COLZ/CDMO ratio and total PANSS score was observed in Taiwanese schizophrenic patients. TDM of both OLZ and DMO levels could assist clinical practice when individualizing OLZ dosage adjustments for patients with schizophrenia.
[Mh] Termos MeSH primário: Benzodiazepinas/sangue
Monitoramento de Medicamentos/métodos
Pirenzepina/análogos & derivados
Esquizofrenia/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Antipsicóticos/administração & dosagem
Antipsicóticos/sangue
Benzodiazepinas/administração & dosagem
Benzodiazepinas/metabolismo
Feminino
Seres Humanos
Masculino
Meia-Idade
Pirenzepina/sangue
Escalas de Graduação Psiquiátrica
Curva ROC
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antipsychotic Agents); 12794-10-4 (Benzodiazepines); 3G0285N20N (Pirenzepine); C1053I7P65 (desmethylolanzapine); N7U69T4SZR (olanzapine)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160206
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0148539


  7 / 3708 MEDLINE  
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[PMID]:26825997
[Au] Autor:Tangsucharit P; Takatori S; Zamami Y; Goda M; Pakdeechote P; Kawasaki H; Takayama F
[Ad] Endereço:Department of Clinical Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
[Ti] Título:Muscarinic acetylcholine receptor M1 and M3 subtypes mediate acetylcholine-induced endothelium-independent vasodilatation in rat mesenteric arteries.
[So] Source:J Pharmacol Sci;130(1):24-32, 2016 Jan.
[Is] ISSN:1347-8648
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:The present study investigated pharmacological characterizations of muscarinic acetylcholine receptor (AChR) subtypes involving ACh-induced endothelium-independent vasodilatation in rat mesenteric arteries. Changes in perfusion pressure to periarterial nerve stimulation and ACh were measured before and after the perfusion of Krebs solution containing muscarinic receptor antagonists. Distributions of muscarinic AChR subtypes in mesenteric arteries with an intact endothelium were studied using Western blotting. The expression level of M1 and M3 was significantly greater than that of M2. Endothelium removal significantly decreased expression levels of M2 and M3, but not M1. In perfused mesenteric vascular beds with intact endothelium and active tone, exogenous ACh (1, 10, and 100 nmol) produced concentration-dependent and long-lasting vasodilatations. In endothelium-denuded preparations, relaxation to ACh (1 nmol) disappeared, but ACh at 10 and 100 nmol caused long-lasting vasodilatations, which were markedly blocked by the treatment of pirenzepine (M1 antagonist) or 4-DAMP (M1 and M3 antagonist) plus hexamethonium (nicotinic AChR antagonist), but not methoctramine (M2 and M4 antagonist). These results suggest that muscarinic AChR subtypes, mainly M1, distribute throughout the rat mesenteric arteries, and that activation of M1 and/or M3 which may be located on CGRPergic nerves releases CGRP, causing an endothelium-independent vasodilatation.
[Mh] Termos MeSH primário: Acetilcolina/farmacologia
Endotélio Vascular
Artérias Mesentéricas/efeitos dos fármacos
Receptor Muscarínico M1/fisiologia
Receptor Muscarínico M3/fisiologia
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcolina/antagonistas & inibidores
Animais
Peptídeo Relacionado com Gene de Calcitonina/secreção
Relação Dose-Resposta a Droga
Hexametônio/farmacologia
Técnicas In Vitro
Masculino
Artérias Mesentéricas/metabolismo
Piperidinas/farmacologia
Pirenzepina/farmacologia
Ratos Wistar
Receptor Muscarínico M1/antagonistas & inibidores
Receptor Muscarínico M1/metabolismo
Receptor Muscarínico M3/antagonistas & inibidores
Receptor Muscarínico M3/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Piperidines); 0 (Receptor, Muscarinic M1); 0 (Receptor, Muscarinic M3); 3C9PSP36Z2 (Hexamethonium); 3G0285N20N (Pirenzepine); 81405-11-0 (4-diphenylacetoxy-1,1-dimethylpiperidinium); 83652-28-2 (Calcitonin Gene-Related Peptide); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:160210
[Lr] Data última revisão:
160210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160131
[St] Status:MEDLINE


  8 / 3708 MEDLINE  
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[PMID]:26823384
[Au] Autor:Zhu Y; Chen SR; Pan HL
[Ad] Endereço:Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
[Ti] Título:Muscarinic receptor subtypes differentially control synaptic input and excitability of cerebellum-projecting medial vestibular nucleus neurons.
[So] Source:J Neurochem;137(2):226-39, 2016 Apr.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it remains unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory post-synaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory post-synaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant post-synaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Pre-synaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. Medial vestibular nucleus (MVN) neurons projecting to the cerebellum are involved in balance control. We found that activation of pre-synaptic M2 muscarinic receptors inhibit glutamatergic input from vestibular primary afferents, whereas stimulation of post-synaptic M3 muscarinic receptors increases the firing activity of cerebellum-projecting MVN neurons. This new information advances our understanding of the cholinergic mechanism regulating the vestibular system.
[Mh] Termos MeSH primário: Cerebelo/citologia
Neurônios/fisiologia
Receptores Muscarínicos/metabolismo
Transmissão Sináptica/fisiologia
Núcleos Vestibulares/citologia
[Mh] Termos MeSH secundário: Alcenos/farmacologia
Animais
Bicuculina/farmacologia
Colinérgicos/farmacologia
Interações Medicamentosas
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos
Antagonistas de Receptores de GABA-A/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Masculino
Neurônios/efeitos dos fármacos
Técnicas de Patch-Clamp
Fosfopiruvato Hidratase/metabolismo
Piperidinas/farmacologia
Pirenzepina/análogos & derivados
Pirenzepina/farmacologia
Piridazinas/farmacologia
Ratos
Ratos Sprague-Dawley
Receptores Muscarínicos/genética
Transmissão Sináptica/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alkenes); 0 (Cholinergic Agents); 0 (GABA-A Receptor Antagonists); 0 (J 104129); 0 (Piperidines); 0 (Pyridazines); 0 (Receptors, Muscarinic); 3G0285N20N (Pirenzepine); 99460MG420 (gabazine); EC 4.2.1.11 (Phosphopyruvate Hydratase); OM7J0XAL0S (otenzepad); Y37615DVKC (Bicuculline)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170403
[Lr] Data última revisão:
170403
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160130
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.13554


  9 / 3708 MEDLINE  
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[PMID]:26518025
[Au] Autor:Higashino K; Ago Y; Umeki T; Hasebe S; Onaka Y; Hashimoto H; Takuma K; Matsuda T
[Ad] Endereço:Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
[Ti] Título:Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice.
[So] Source:Psychopharmacology (Berl);233(3):521-8, 2016 Feb.
[Is] ISSN:1432-2072
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:RATIONALE: The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice. OBJECTIVES: We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice. METHODS: Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured. RESULTS: Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors. CONCLUSIONS: Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.
[Mh] Termos MeSH primário: Inibidores da Colinesterase/farmacologia
Receptores Muscarínicos/efeitos dos fármacos
Reflexo de Sobressalto/efeitos dos fármacos
Rivastigmina/farmacologia
Isolamento Social/psicologia
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Estimulação Acústica
Animais
Química Encefálica/efeitos dos fármacos
Dopamina/metabolismo
Masculino
Mecamilamina/farmacologia
Camundongos
Antagonistas Muscarínicos/farmacologia
Antagonistas Nicotínicos/farmacologia
Pirenzepina/análogos & derivados
Pirenzepina/farmacologia
Córtex Pré-Frontal/efeitos dos fármacos
Córtex Pré-Frontal/metabolismo
Receptor 5-HT1A de Serotonina/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Muscarinic Antagonists); 0 (Nicotinic Antagonists); 0 (Receptors, Muscarinic); 0990EG3K10 (telenzepine); 112692-38-3 (Receptor, Serotonin, 5-HT1A); 3G0285N20N (Pirenzepine); 6EE945D3OK (Mecamylamine); N9YNS0M02X (Acetylcholine); PKI06M3IW0 (Rivastigmine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151101
[St] Status:MEDLINE
[do] DOI:10.1007/s00213-015-4123-7


  10 / 3708 MEDLINE  
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[PMID]:26511338
[Au] Autor:Dean B; Hopper S; Conn PJ; Scarr E
[Ad] Endereço:The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia.
[Ti] Título:Changes in BQCA Allosteric Modulation of [(3)H]NMS Binding to Human Cortex within Schizophrenia and by Divalent Cations.
[So] Source:Neuropsychopharmacology;41(6):1620-8, 2016 May.
[Is] ISSN:1740-634X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Stimulation of the cortical muscarinic M1 receptor (CHRM1) is proposed as a treatment for schizophrenia, a hypothesis testable using CHRM1 allosteric modulators. Allosteric modulators have been shown to change the activity of CHRMs using cloned human CHRMs and CHRM knockout mice but not human CNS, a prerequisite for them working in humans. Here we show in vitro that BQCA, a positive allosteric CHRM1 modulator, brings about the expected change in affinity of the CHRM1 orthosteric site for acetylcholine in human cortex. Moreover, this effect of BQCA is reduced in the cortex of a subset of subjects with schizophrenia, separated into a discrete population because of a profound loss of cortical [(3)H]pirenzepine binding. Surprisingly, there was no change in [(3)H]NMS binding to the cortex from this subset or those with schizophrenia but without a marked loss of cortical CHRM1. Hence, we explored the nature of [(3)H]pirenzepine and [(3)H]NMS binding to human cortex and showed total [(3)H]pirenzepine and [(3)H]NMS binding was reduced by Zn(2+), acetylcholine displacement of [(3)H]NMS binding was enhanced by Mg(2+) and Zn(2+), acetylcholine displacement of [(3)H]pirenzepine was reduced by Mg(2+) and enhanced by Zn(2+), whereas BQCA effects on [(3)H]NMS, but not [(3)H]pirenzepine, binding was enhanced by Mg(2+) and Zn(2+). These data suggest the orthosteric and allosteric sites on CHRMs respond differently to divalent cations and the effects of allosteric modulation of the cortical CHRM1 is reduced in a subset of people with schizophrenia, a finding that may have ramifications for the use of CHRM1 allosteric modulators in the treatment of schizophrenia.
[Mh] Termos MeSH primário: Cátions Bivalentes/farmacologia
Córtex Cerebral/metabolismo
N-Metilescopolamina/metabolismo
Quinolinas/farmacologia
Receptores Muscarínicos/efeitos dos fármacos
Esquizofrenia/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/fisiologia
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/fisiopatologia
Feminino
Seres Humanos
Masculino
Meia-Idade
Pirenzepina/farmacologia
Receptor Muscarínico M1
Receptores Muscarínicos/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid); 0 (CHRM1 protein, human); 0 (Cations, Divalent); 0 (Quinolines); 0 (Receptor, Muscarinic M1); 0 (Receptors, Muscarinic); 3G0285N20N (Pirenzepine); VDR09VTQ8U (N-Methylscopolamine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151030
[St] Status:MEDLINE
[do] DOI:10.1038/npp.2015.330



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