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[PMID]:28457669
[Au] Autor:Kamens HM; Peck C; Garrity C; Gechlik A; Jenkins BC; Rajan A
[Ad] Endereço:Department of Biobehavioral Health, Penn State University, University Park, PA, USA; Center for Brain, Behavior, and Cognition, Penn State University, University Park, PA, USA. Electronic address: hmk123@psu.edu.
[Ti] Título:α6ß2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption.
[So] Source:Alcohol;61:43-49, 2017 Jun.
[Is] ISSN:1873-6823
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system have been implicated in ethanol behaviors. In particular, work in genetically engineered mice has demonstrated that α6-containing nAChRs are involved in ethanol consumption and sedation. A limitation of these studies is that the alteration in the receptor was present throughout development. The recently described α6ß2 antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), now makes it possible to test for the involvement of these receptors using a pharmacological approach. The aim of this study was to examine the role of α6ß2 nAChRs in ethanol behaviors using a pharmacological approach. Adolescent C57BL/6J mice were treated with bPiDI 30 min prior to testing the mice for binge-like ethanol consumption in the drinking-in-the-dark (DID) test, ethanol-induced motor incoordination using the balance beam, and ethanol-induced sedation using the Loss of Righting Reflex (LORR) paradigm. Adolescent animals were chosen because they express a high amount of α6 mRNA relative to adult animals. Control studies were also performed to determine the effect of bPiDI on locomotor activity and ethanol metabolism. Female mice treated with 20 mg/kg bPiDI had reduced locomotor activity compared to saline-treated animals during the first 30 min following an acute injection. Pretreatment with the α6ß2 antagonist reduced adolescent ethanol consumption but also reduced saccharin consumption. No significant effects were observed on ethanol-induced ataxia, sedation, or metabolism. This study provides evidence that α6ß2 nAChRs are involved in locomotor activity as well as ethanol and saccharin consumption in adolescent animals.
[Mh] Termos MeSH primário: Consumo de Bebidas Alcoólicas/fisiopatologia
Etanol/administração & dosagem
Locomoção/efeitos dos fármacos
Receptores Nicotínicos/fisiologia
[Mh] Termos MeSH secundário: Consumo de Bebidas Alcoólicas/prevenção & controle
Animais
Bebedeira/fisiopatologia
Etanol/efeitos adversos
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Antagonistas Nicotínicos/farmacologia
Picolinas/farmacologia
Compostos de Piridínio/farmacologia
Sacarina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (N,N-decane-1,10-diyl-bis-3-picolinium); 0 (Nicotinic Antagonists); 0 (Picolines); 0 (Pyridinium Compounds); 0 (Receptors, Nicotinic); 0 (alpha6beta2 nicotinic acetylcholine receptor); 3K9958V90M (Ethanol); FST467XS7D (Saccharin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


  2 / 2903 MEDLINE  
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[PMID]:28470123
[Au] Autor:Dojo K; Yamaguchi Y; Fustin JM; Doi M; Kobayashi M; Okamura H
[Ad] Endereço:Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
[Ti] Título:Carbachol Induces Phase-dependent Phase Shifts of Per1 Transcription Rhythms in Cultured Suprachiasmatic Nucleus Slices.
[So] Source:J Biol Rhythms;32(2):101-108, 2017 Apr.
[Is] ISSN:1552-4531
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Among nonphotic stimulants, a classic cholinergic agonist, carbachol, is known to have a strong and unique phase-resetting effect on the circadian clock: Intracerebroventricular carbachol treatment causes phase delays during the subjective early night and phase advances in the subjective late night, but the effects of this drug on the suprachiasmatic nucleus (SCN) in vivo and in vitro are still controversial. In the present study, we succeeded in reproducing the biphasic phase-shifting effect of carbachol on clock gene expression in organotypic SCN slices prepared from mice carrying a Per1-promoter fused luciferase gene ( Per1-luc). Since this biphasic effect of carbachol in Per1-luc SCN was prevented by atropine but not by mecamylamine, we concluded that these phase shifts were muscarinic receptor-dependent. Next, we analyzed the expression of muscarinic receptors in the SCN by in situ hybridization and found that M3 and M4 subtypes were expressed in SCN cells. These signals appeared neonatally and reached adult levels at postnatal day 10. Together, these findings suggest that carbachol has a phase-dependent phase-shifting effect on the SCN clock through muscarinic receptor subtypes expressed in the SCN.
[Mh] Termos MeSH primário: Carbacol/farmacologia
Agonistas Colinérgicos/farmacologia
Ritmo Circadiano/efeitos dos fármacos
Proteínas Circadianas Period/genética
Núcleo Supraquiasmático/efeitos dos fármacos
Núcleo Supraquiasmático/fisiologia
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Atropina/farmacologia
Relógios Circadianos/efeitos dos fármacos
Expressão Gênica
Luciferases/genética
Mecamilamina/farmacologia
Camundongos
Atividade Motora
Antagonistas Muscarínicos/farmacologia
Antagonistas Nicotínicos/farmacologia
Técnicas de Cultura de Órgãos
Regiões Promotoras Genéticas
Receptores Muscarínicos/genética
Receptores Muscarínicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinergic Agonists); 0 (Muscarinic Antagonists); 0 (Nicotinic Antagonists); 0 (Per1 protein, mouse); 0 (Period Circadian Proteins); 0 (Receptors, Muscarinic); 6EE945D3OK (Mecamylamine); 7C0697DR9I (Atropine); 8Y164V895Y (Carbachol); EC 1.13.12.- (Luciferases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180126
[Lr] Data última revisão:
180126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1177/0748730417691205


  3 / 2903 MEDLINE  
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[PMID]:28838693
[Au] Autor:Jin Y; Huang X; Papke RL; Jutkiewicz EM; Showalter HD; Zhan CG
[Ad] Endereço:Department of Medicinal Chemistry and Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, United States.
[Ti] Título:Design, synthesis, and biological activity of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors.
[So] Source:Bioorg Med Chem Lett;27(18):4350-4353, 2017 09 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridines (3a-3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then subsequent modifications were made on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist, which is highly selective for α3ß4 nAChR (K =123nM) over the α4ß2 and α7 receptors.
[Mh] Termos MeSH primário: Desenho de Drogas
Antagonistas Nicotínicos/farmacologia
Piridinas/farmacologia
Receptores Nicotínicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Antagonistas Nicotínicos/síntese química
Antagonistas Nicotínicos/química
Piridinas/síntese química
Piridinas/química
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Nicotinic Antagonists); 0 (Pyridines); 0 (Receptors, Nicotinic); NH9L3PP67S (pyridine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE


  4 / 2903 MEDLINE  
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[PMID]:28820587
[Au] Autor:Onozaki Y; Horikoshi R; Ohno I; Kitsuda S; Durkin KA; Suzuki T; Asahara C; Hiroki N; Komabashiri R; Shimizu R; Furutani S; Ihara M; Matsuda K; Mitomi M; Kagabu S; Uomoto K; Tomizawa M
[Ad] Endereço:Agricultural and Veterinary Research Laboratories, Agricultural and Veterinary Division, Meiji Seika Pharma Co., Ltd. , Yokohama, Kanagawa 222-8567, Japan.
[Ti] Título:Flupyrimin: A Novel Insecticide Acting at the Nicotinic Acetylcholine Receptors.
[So] Source:J Agric Food Chem;65(36):7865-7873, 2017 Sep 13.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel chemotype insecticide flupyrimin (FLP) [N-[(E)-1-(6-chloro-3-pyridinylmethyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide], discovered by Meiji Seika Pharma, has unique biological properties, including outstanding potency to imidacloprid (IMI)-resistant rice pests together with superior safety toward pollinators. Intriguingly, FLP acts as a nicotinic antagonist in American cockroach neurons, and [ H]FLP binds to the multiple high-affinity binding components in house fly nicotinic acetylcholine (ACh) receptor (nAChR) preparation. One of the [ H]FLP receptors is identical to the IMI receptor, and the alternative is IMI-insensitive subtype. Furthermore, FLP is favorably safe to rats as predicted by the very low affinity to the rat α4ß2 nAChR. Structure-activity relationships of FLP analogues in terms of receptor potency, featuring the pyridinylidene and trifluoroacetyl pharmacophores, were examined, thereby establishing the FLP molecular recognition at the Aplysia californica ACh-binding protein, a suitable structural surrogate of the insect nAChR. These FLP pharmacophores account for the excellent receptor affinity, accordingly revealing differences in its binding mechanism from IMI.
[Mh] Termos MeSH primário: Inseticidas/química
Inseticidas/farmacologia
Antagonistas Nicotínicos/química
Antagonistas Nicotínicos/farmacologia
Receptores Nicotínicos/química
[Mh] Termos MeSH secundário: Animais
Aplysia/efeitos dos fármacos
Aplysia/metabolismo
Sítios de Ligação
Proteínas de Insetos/química
Proteínas de Insetos/metabolismo
Cinética
Periplaneta/efeitos dos fármacos
Periplaneta/genética
Periplaneta/metabolismo
Ratos
Receptores Nicotínicos/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insect Proteins); 0 (Insecticides); 0 (Nicotinic Antagonists); 0 (Receptors, Nicotinic)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b02924


  5 / 2903 MEDLINE  
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[PMID]:28815595
[Au] Autor:Brindley RL; Bauer MB; Hartley ND; Horning KJ; Currie KPM
[Ad] Endereço:Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
[Ti] Título:Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.
[So] Source:J Neurochem;143(2):171-182, 2017 Oct.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 µM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca entry via nAChRs.
[Mh] Termos MeSH primário: Medula Suprarrenal/secreção
Catecolaminas/secreção
Células Cromafins/secreção
Antagonistas Nicotínicos/farmacologia
Receptores Nicotínicos/fisiologia
Receptores sigma/fisiologia
[Mh] Termos MeSH secundário: Medula Suprarrenal/citologia
Medula Suprarrenal/efeitos dos fármacos
Animais
Anisóis/farmacologia
Catecolaminas/antagonistas & inibidores
Bovinos
Células Cultivadas
Células Cromafins/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ligantes
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Propilaminas/farmacologia
Receptores sigma/agonistas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anisoles); 0 (Catecholamines); 0 (Ligands); 0 (Nicotinic Antagonists); 0 (Propylamines); 0 (Receptors, Nicotinic); 0 (Receptors, sigma); 0 (sigma-1 receptor); 149409-57-4 (N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14149


  6 / 2903 MEDLINE  
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[PMID]:28630263
[Au] Autor:Jin X; Germann AL; Shin DJ; Akk G; Steinbach JH
[Ad] Endereço:Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri (X.J., A.L.G., D.J.S., G.A., J.H.S.); and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri (G.A., J.H.S.).
[Ti] Título:Determination of the Residues in the Extracellular Domain of the Nicotinic Subunit Required for the Actions of Physostigmine on Neuronal Nicotinic Receptors.
[So] Source:Mol Pharmacol;92(3):318-326, 2017 Sep.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Physostigmine can potentiate and inhibit neuronal nicotinic receptors, in addition to inhibiting the activity of acetylcholinesterase. We found that receptors containing three copies of the 2 subunit are inhibited by low concentrations of physostigmine in contrast to receptors containing three copies of the 4 subunit that are potentiated. We exploited this observation to determine the regions required for the actions of physostigmine. Chimeric constructs of the 2 and 4 subunits located two regions in the extracellular amino-terminal domain of the subunit: the E loop (a loop of the transmitter-binding domain) and a region closer to the amino-terminus that collectively could completely determine the different effects of physostigmine. Point mutations then identified a single residue, 2(I92) versus 4(R92), that, when combined with transfer of the E loop, could convert the inhibition seen with 2 subunits to potentiation and the potentiation seen with 4 subunits to inhibition. In addition, other point mutations could affect the extent of potentiation or inhibition, indicating that a more extensive set of interactions in the amino-terminal domain plays some role in the actions of physostigmine.
[Mh] Termos MeSH primário: Antagonistas Nicotínicos/farmacologia
Fisostigmina/farmacologia
Receptores Nicotínicos/química
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Camundongos
Domínios Proteicos
Subunidades Proteicas
Receptores Nicotínicos/efeitos dos fármacos
Relação Estrutura-Atividade
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nicotinic Antagonists); 0 (Protein Subunits); 0 (Receptors, Nicotinic); 9U1VM840SP (Physostigmine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1124/mol.117.108894


  7 / 2903 MEDLINE  
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[PMID]:28606623
[Au] Autor:Donvito G; Bagdas D; Toma W; Rahimpour E; Jackson A; Meade JA; AlSharari S; Kulkarni AR; Ivy Carroll F; Lichtman AH; Papke RL; Thakur GA; Imad Damaj M
[Ad] Endereço:Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: giulia.donvito@vcuhealth.org.
[Ti] Título:The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice.
[So] Source:Exp Neurol;295:194-201, 2017 Sep.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recently, α7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and α7-silent agonists. Activation of α7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-α (PPAR-α), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca -dependent manner. Here, we investigated potential crosstalk between α7 nAChR and PPAR-α, using the formalin test, a mouse model of tonic pain. Using pharmacological and genetic approaches, we found that PNU282987, a full α7 agonist, attenuated formalin-induced nociceptive behavior in α7-dependent manner. Interestingly, the selective PPAR-α antagonist GW6471 blocked the antinociceptive effects of PNU282987, but did not alter the antinociceptive responses evoked by the α7 nAChR PAM PNU120596, ago-PAM GAT107, and silent agonist NS6740. Moreover, GW6471 administered systemically or spinally, but not via the intraplantar surface of the formalin-injected paw blocked PNU282987-induced antinociception. Conversely, exogenous administration of the naturally occurring PPAR-α agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid CB antagonist rimonabant and the CB antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR-α plays a key role in a putative antinociceptive α7 nicotinic signaling pathway.
[Mh] Termos MeSH primário: Nociceptividade/efeitos dos fármacos
PPAR alfa/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Compostos Azabicíclicos/farmacologia
Benzamidas/farmacologia
Compostos Bicíclicos com Pontes/farmacologia
Antagonistas de Receptores de Canabinoides/farmacologia
Etanolaminas/farmacologia
Furanos/farmacologia
Masculino
Camundongos
Camundongos Endogâmicos ICR
Antagonistas Nicotínicos/farmacologia
Oxazóis/farmacologia
PPAR alfa/antagonistas & inibidores
Medição da Dor/efeitos dos fármacos
Ácidos Palmíticos/farmacologia
Receptor Cross-Talk
Tirosina/análogos & derivados
Tirosina/farmacologia
Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1,4-diazabicyclo(3.2.2)nonan-4-yl(5-(3-(trifluoromethyl)phenyl)furan-2-yl)methanone); 0 (Azabicyclo Compounds); 0 (Benzamides); 0 (Bridged Bicyclo Compounds); 0 (Cannabinoid Receptor Antagonists); 0 (Ethanolamines); 0 (Furans); 0 (GW 6471); 0 (Nicotinic Antagonists); 0 (Oxazoles); 0 (PNU-282987); 0 (PPAR alpha); 0 (Palmitic Acids); 0 (alpha7 Nicotinic Acetylcholine Receptor); 42HK56048U (Tyrosine); 6R8T1UDM3V (palmidrol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE


  8 / 2903 MEDLINE  
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[PMID]:28603989
[Au] Autor:Wu Y; Zhangsun D; Zhu X; Kaas Q; Zhangsun M; Harvey PJ; Craik DJ; McIntosh JM; Luo S
[Ad] Endereço:Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Lab for Marine Drugs of Haikou, Hainan University , Haikou, Hainan 570228 China.
[Ti] Título:α-Conotoxin [S9A]TxID Potently Discriminates between α3ß4 and α6/α3ß4 Nicotinic Acetylcholine Receptors.
[So] Source:J Med Chem;60(13):5826-5833, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:α3ß4 nAChRs have been implicated in various pathophysiological conditions. However, the expression profile of α3ß4 nAChRs and α6/α3ß4 nAChRs overlap in a variety of tissues. To distinguish between these two subtypes, we redesigned peptide 1 (α-conotoxin TxID), which inhibits α3ß4 and α6/α3ß4 nAChR subtypes. We systematically mutated 1 to evaluate analogue selectivity for α3ß4 vs α6/α3ß4 nAChRs expressed in Xenopus laevis oocytes. One analogue, peptide 7 ([S9A]TxID), had 46-fold greater potency for α3ß4 versus α6/α3ß4 nAChRs. Peptide 7 had IC s > 10 µM for other nAChR subtypes. Molecular dynamics simulations suggested that Ser-9 of TxID was involved in a weak hydrogen bond with ß4 Lys-81 in the α6ß4 binding site but not in the α3ß4 binding site. When Ser-9 was substituted by an Ala, this hydrogen bond interaction was disrupted. These results provide further molecular insights into the selectivity of 7 and provide a guide for designing ligands that block α3ß4 nAChRs.
[Mh] Termos MeSH primário: Conotoxinas/farmacologia
Antagonistas Nicotínicos/farmacologia
Receptores Nicotínicos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Conotoxinas/química
Caramujo Conus/química
Espectroscopia de Ressonância Magnética
Simulação de Dinâmica Molecular
Antagonistas Nicotínicos/química
Oócitos/metabolismo
Peptídeos/química
Peptídeos/farmacologia
Ratos
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins); 0 (Nicotinic Antagonists); 0 (Peptides); 0 (Receptors, Nicotinic); 0 (nicotinic receptor alpha3beta4); 0 (nicotinic receptor alpha6)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00546


  9 / 2903 MEDLINE  
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[PMID]:28433565
[Au] Autor:Li X; Horishita T; Toyohira Y; Shao H; Bai J; Bo H; Song X; Ishikane S; Yoshinaga Y; Satoh N; Tsutsui M; Yanagihara N
[Ad] Endereço:Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
[Ti] Título:Inhibitory effects of pine nodule extract and its component, SJ-2, on acetylcholine-induced catecholamine secretion and synthesis in bovine adrenal medullary cells.
[So] Source:J Pharmacol Sci;133(4):268-275, 2017 Apr.
[Is] ISSN:1347-8648
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Extract of pine nodules (matsufushi) formed by bark proliferation on the surface of trees of Pinus tabulaeformis or Pinus massoniana has been used as an analgesic for joint pain, rheumatism, neuralgia, dysmenorrhea and other complaints in Chinese traditional medicine. Here we report the effects of matsufushi extract and its components on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that matsufushi extract (0.0003-0.005%) and its component, SJ-2 (5-hydroxy-3-methoxy-trans-stilbene) (0.3-100 µM), but not the other three, concentration-dependently inhibited catecholamine secretion induced by acetylcholine, a physiological secretagogue. Matsufushi extract (0.0003-0.005%) and SJ-2 (0.3-100 µM) also inhibited Ca influx induced by acetylcholine in a concentration-dependent manner, similar to its effect on catecholamine secretion. They also suppressed C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, matsufushi extract (0.00003-0.001%) and SJ-2 (1-100 µM) directly inhibited the current evoked by acetylcholine. The present findings suggest that SJ-2, as well as matsufushi extract, inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.
[Mh] Termos MeSH primário: Acetilcolina/farmacologia
Medula Suprarrenal/citologia
Medula Suprarrenal/metabolismo
Catecolaminas/biossíntese
Catecolaminas/secreção
Pinus/química
Extratos Vegetais/química
Extratos Vegetais/farmacologia
Estilbenos/farmacologia
[Mh] Termos MeSH secundário: Acetilcolina/antagonistas & inibidores
Animais
Cálcio/metabolismo
Bovinos
Células Cultivadas
Relação Dose-Resposta a Droga
Antagonistas Nicotínicos
Extratos Vegetais/isolamento & purificação
Receptores Nicotínicos/metabolismo
Tirosina 3-Mono-Oxigenase/metabolismo
Xenopus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-hydroxy-3-methoxystilbene); 0 (Catecholamines); 0 (Nicotinic Antagonists); 0 (Plant Extracts); 0 (Receptors, Nicotinic); 0 (Stilbenes); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); N9YNS0M02X (Acetylcholine); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170424
[St] Status:MEDLINE


  10 / 2903 MEDLINE  
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[PMID]:28398760
[Au] Autor:Bai X; Stitzel JA; Bai A; Zambrano CA; Phillips M; Marrack P; Chan ED
[Ad] Endereço:1 Department of Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado.
[Ti] Título:Nicotine Impairs Macrophage Control of Mycobacterium tuberculosis.
[So] Source:Am J Respir Cell Mol Biol;57(3):324-333, 2017 Sep.
[Is] ISSN:1535-4989
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pure nicotine impairs macrophage killing of Mycobacterium tuberculosis (MTB), but it is not known whether the nicotine component in cigarette smoke (CS) plays a role. Moreover, the mechanisms by which nicotine impairs macrophage immunity against MTB have not been explored. To neutralize the effects of nicotine in CS extract, we used a competitive inhibitor to the nicotinic acetylcholine receptor (nAChR)-mecamylamine-as well as macrophages derived from mice with genetic disruption of specific subunits of nAChR. We also determined whether nicotine impaired macrophage autophagy and whether nicotine-exposed T regulatory cells (Tregs) could subvert macrophage anti-MTB immunity. Mecamylamine reduced the CS extract increase in MTB burden by 43%. CS extract increase in MTB was also significantly attenuated in macrophages from mice with genetic disruption of either the α7, ß2, or ß4 subunit of nAChR. Nicotine inhibited autophagosome formation in MTB-infected THP-1 cells and primary murine alveolar macrophages, as well as increased the intracellular MTB burden. Nicotine increased migration of THP-1 cells, consistent with the increased number of macrophages found in the lungs of smokers. Nicotine induced Tregs to produce transforming growth factor-ß. Naive mouse macrophages co-cultured with nicotine-exposed Tregs had significantly greater numbers of viable MTB recovered with increased IL-10 production and urea production, but no difference in secreted nitric oxide as compared with macrophages cocultured with unexposed Tregs. We conclude that nicotine in CS plays an important role in subverting macrophage control of MTB infection.
[Mh] Termos MeSH primário: Macrófagos Alveolares/microbiologia
Mycobacterium tuberculosis/efeitos dos fármacos
Nicotina/farmacologia
[Mh] Termos MeSH secundário: Autofagossomos/efeitos dos fármacos
Autofagossomos/metabolismo
Autofagia/efeitos dos fármacos
Linhagem Celular
Movimento Celular/efeitos dos fármacos
Seres Humanos
Macrófagos Alveolares/efeitos dos fármacos
NF-kappa B/metabolismo
Antagonistas Nicotínicos/farmacologia
Subunidades Proteicas/metabolismo
Receptores Nicotínicos/metabolismo
Fumar
Linfócitos T Reguladores/efeitos dos fármacos
Linfócitos T Reguladores/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NF-kappa B); 0 (Nicotinic Antagonists); 0 (Protein Subunits); 0 (Receptors, Nicotinic); 6M3C89ZY6R (Nicotine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE
[do] DOI:10.1165/rcmb.2016-0270OC



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