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[PMID]:29177353
[Au] Autor:Shah R; Zhou A; Wagner CR
[Ad] Endereço:Department of Medicinal Chemistry University of Minnesota, USA. wagne003@umn.edu.
[Ti] Título:Switch-on fluorescent/FRET probes to study human histidine triad nucleotide binding protein 1 (hHint1), a novel target for opioid tolerance and neuropathic pain.
[So] Source:Org Biomol Chem;15(48):10230-10237, 2017 Dec 13.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Histidine Triad Nucleotide Binding Protein 1 (Hint1) has emerged to be an important post-synaptic protein associated with a variety of central nervous system disorders such as pain, addiction, and schizophrenia. Recently, inhibition of histidine nucleotide binding protein 1 (Hint1) with a small nucleoside inhibitor has shown promise as a new therapeutic strategy for the treatment of neuropathic pain. Herein, we describe the first rationally designed small molecule switch-on probes with dual fluorescence and FRET properties to study Hint1. Two non-natural fluorescent nucleosides with a fluorescent lifetime of 20 and 25 ns were each coupled through a linker to the indole ring, i.e. probes 7 and 8. Both probes were found to be water soluble and quenched intramolecularly via photoinduced electron transfer (PET) resulting in minimal background fluorescence. Upon incubating with Hint1, compound 7 and 8 exhibited a 40- and 16-fold increase in the fluorescence intensity compared to the control. Compounds 7 and 8 bind Hint1 with a dissociation constant of 0.121 ± 0.02 and 2.2 ± 0.36 µM, respectively. We demonstrate that probe 8 exhibits a switch-on FRET property with an active site tryptophan residue (W123). We show the utility of probes in performing quantitative ligand displacement studies, as well as in selective detection of Hint1 in the cell lysates. These probes should be useful for studying the dynamics of the active site, as well as for the development of fluorescence lifetime based high throughput screening assay to identify novel inhibitors for Hint1 in future.
[Mh] Termos MeSH primário: Transferência Ressonante de Energia de Fluorescência
Fluorescência
Corantes Fluorescentes/química
Proteínas do Tecido Nervoso/química
Neuralgia/tratamento farmacológico
Receptores Opioides/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Corantes Fluorescentes/síntese química
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (HINT1 protein, human); 0 (Nerve Tissue Proteins); 0 (Receptors, Opioid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob02472j


  2 / 12476 MEDLINE  
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[PMID]:29316911
[Au] Autor:Caputi FF; Acquas E; Kasture S; Ruiu S; Candeletti S; Romualdi P
[Ad] Endereço:Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. francesca.caputi3@unibo.it.
[Ti] Título:The standardized Withania somnifera Dunal root extract alters basal and morphine-induced opioid receptor gene expression changes in neuroblastoma cells.
[So] Source:BMC Complement Altern Med;18(1):9, 2018 Jan 10.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Behavioral studies demonstrated that the administration of Withania somnifera Dunal roots extract (WSE), prolongs morphine-elicited analgesia and reduces the development of tolerance to the morphine's analgesic effect; however, little is known about the underpinning molecular mechanism(s). In order to shed light on this issue in the present paper we explored whether WSE promotes alterations of µ (MOP) and nociceptin (NOP) opioid receptors gene expression in neuroblastoma SH-SY5Y cells. METHODS: A range of WSE concentrations was preliminarily tested to evaluate their effects on cell viability. Subsequently, the effects of 5 h exposure to WSE (0.25, 0.50 and 1.00 mg/ml), applied alone and in combination with morphine or naloxone, on MOP and NOP mRNA levels were investigated. RESULTS: Data analysis revealed that morphine decreased MOP and NOP receptor gene expression, whereas naloxone elicited their up-regulation. In addition, pre-treatment with naloxone prevented the morphine-elicited gene expression alterations. Interestingly, WSE was able to: a) alter MOP but not NOP gene expression; b) counteract, at its highest concentration, morphine-induced MOP down-regulation, and c) hamper naloxone-induced MOP and NOP up-regulation. CONCLUSION: Present in-vitro data disclose novel evidence about the ability of WSE to influence MOP and NOP opioid receptors gene expression in SH-SY5Y cells. Moreover, our findings suggest that the in-vivo modulation of morphine-mediated analgesia by WSE could be related to the hindering of morphine-elicited opioid receptors down-regulation here observed following WSE pre-treatment at its highest concentration.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Neuroblastoma/metabolismo
Extratos Vegetais/farmacologia
Receptores Opioides/metabolismo
Withania/química
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular
Seres Humanos
Extratos Vegetais/química
Raízes de Plantas/química
Reação em Cadeia da Polimerase em Tempo Real
Receptores Opioides/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plant Extracts); 0 (Receptors, Opioid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-2065-9


  3 / 12476 MEDLINE  
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[PMID]:28966276
[Au] Autor:Ishikawa K; Karaki F; Tayama K; Higashi E; Hirayama S; Itoh K; Fujii H
[Ad] Endereço:Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
[Ti] Título:C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics.
[So] Source:Chem Pharm Bull (Tokyo);65(10):920-929, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the µ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.
[Mh] Termos MeSH primário: Analgésicos Opioides/química
Morfinanos/química
[Mh] Termos MeSH secundário: Analgésicos Opioides/síntese química
Animais
Buprenorfina/análogos & derivados
Buprenorfina/química
Células CHO
Cricetinae
Cricetulus
Ciclização
Seres Humanos
Cinética
Conformação Molecular
Morfinanos/síntese química
Ligação Proteica
Receptores Opioides/química
Receptores Opioides/genética
Receptores Opioides/metabolismo
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Morphinans); 0 (Receptors, Opioid); 0 (Recombinant Proteins); 40D3SCR4GZ (Buprenorphine); 7E53B4O073 (norbuprenorphine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00385


  4 / 12476 MEDLINE  
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[PMID]:28930716
[Au] Autor:Mao Y; Li Z; Chen K; Yu H; Zhang S; Jiang M; Ma Y; Liang C; Liu H; Li H; Hua Q; Zhou H; Sun Y; Fan X
[Ad] Endereço:Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, China.
[Ti] Título:Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems.
[So] Source:Cell Physiol Biochem;43(2):518-530, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Irritable bowel syndrome (IBS), defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. METHODS: Maternal deprivation (MD) was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD) was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg) subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L) and naloxone (100 nmol/L) were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α) and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1) and µ and κ opioid receptors (MOR and KOR) in colon, dorsal root ganglion (DRG) and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analyses and immunofluorescence. RESULTS: Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG) and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. CONCLUSION: The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS.
[Mh] Termos MeSH primário: Analgésicos/uso terapêutico
Colo/efeitos dos fármacos
Grelina/uso terapêutico
Síndrome do Intestino Irritável/tratamento farmacológico
Receptores Opioides/análise
Canais de Cátion TRPV/análise
Dor Visceral/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Animais
Colo/metabolismo
Colo/patologia
Feminino
Gânglios Espinais
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Síndrome do Intestino Irritável/complicações
Síndrome do Intestino Irritável/genética
Síndrome do Intestino Irritável/patologia
Masculino
Meia-Idade
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase em Tempo Real
Receptores Opioides/genética
Canais de Cátion TRPV/genética
Dor Visceral/complicações
Dor Visceral/genética
Dor Visceral/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Ghrelin); 0 (Receptors, Opioid); 0 (TRPV Cation Channels)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1159/000480478


  5 / 12476 MEDLINE  
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[PMID]:28693915
[Au] Autor:Stockdale DP; Titunick MB; Biegler JM; Reed JL; Hartung AM; Wiemer DF; McLaughlin PJ; Neighbors JD
[Ad] Endereço:Department of Chemistry, The University of Iowa, Iowa City, IA 52242-1294, United States.
[Ti] Título:Selective opioid growth factor receptor antagonists based on a stilbene isostere.
[So] Source:Bioorg Med Chem;25(16):4464-4474, 2017 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As part of an ongoing drug development effort aimed at selective opioid receptor ligands based on the pawhuskin natural products we have synthesized a small set of amide isosteres. These amides were centered on lead compounds which are selective antagonists for the delta and kappa opioid receptors. The amide isomers revealed here show dramatically different activity from the parent stilbene compounds. Three of the isomers synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by "low-dose" naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn's disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study.
[Mh] Termos MeSH primário: Amidas/farmacologia
Receptores Opioides/metabolismo
[Mh] Termos MeSH secundário: Amidas/síntese química
Amidas/química
Animais
Células COS
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Cercopithecus aethiops
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Receptors, Opioid); 0 (methionine-enkephalin receptor)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE


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[PMID]:28583844
[Au] Autor:Bedini A; Baiula M; Vincelli G; Formaggio F; Lombardi S; Caprini M; Spampinato S
[Ad] Endereço:Department of Pharmacy and Biotechnology, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
[Ti] Título:Nociceptin/orphanin FQ antagonizes lipopolysaccharide-stimulated proliferation, migration and inflammatory signaling in human glioblastoma U87 cells.
[So] Source:Biochem Pharmacol;140:89-104, 2017 Sep 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G-protein coupled receptors (GPCRs) have gained interest in anti-tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation. A proteomic analysis showed that the nociceptin receptor (NOPr) is among the GPCRs significantly expressed in glioblastoma cells, including U87 cells. We describe a novel role of the peptide nociceptin (N/OFQ), the endogenous ligand of the NOPr that counteracts cell migration, proliferation and increase in IL-1ß mRNA elicited by LPS via TLR4 in U87 glioblastoma cells. Signaling pathways through which N/OFQ inhibits LPS-mediated cell migration and elevation of [Ca ] require ß-arrestin 2 and are sensitive to TNFR-associated factor 6, c-Src and protein kinase C (PKC). LPS-induced cell proliferation and increase in IL-1ß mRNA are counteracted by N/OFQ via ß-arrestin 2, PKC and extracellular signal-regulated kinase 1/2; furthermore, the contributions of the transcription factors NF-kB and AP-1 were investigated. Independent of LPS, N/OFQ induces a significant increase in cell apoptosis. Contrary to what was observed in other cell models, a prolonged exposure to this endotoxin did not promote any tolerance of the cellular effects above described, including NOPr down-regulation while N/OFQ loses its inhibitory role.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia
Antineoplásicos/farmacologia
Glioblastoma/tratamento farmacológico
Peptídeos Opioides/farmacologia
Fator 6 Associado a Receptor de TNF/agonistas
Receptor 4 Toll-Like/antagonistas & inibidores
beta-Arrestina 2/agonistas
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Astrócitos/efeitos dos fármacos
Astrócitos/imunologia
Astrócitos/metabolismo
Astrócitos/patologia
Sinalização do Cálcio/efeitos dos fármacos
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica
Glioblastoma/imunologia
Glioblastoma/metabolismo
Glioblastoma/patologia
Seres Humanos
Interleucina-1beta/agonistas
Interleucina-1beta/antagonistas & inibidores
Interleucina-1beta/genética
Interleucina-1beta/metabolismo
Ligantes
Lipopolissacarídeos/antagonistas & inibidores
Lipopolissacarídeos/toxicidade
Proteínas de Neoplasias/agonistas
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/metabolismo
Proteínas do Tecido Nervoso/agonistas
Proteínas do Tecido Nervoso/antagonistas & inibidores
Proteínas do Tecido Nervoso/metabolismo
Interferência de RNA
Receptores Opioides/agonistas
Receptores Opioides/genética
Fator 6 Associado a Receptor de TNF/antagonistas & inibidores
Fator 6 Associado a Receptor de TNF/genética
Fator 6 Associado a Receptor de TNF/metabolismo
Receptor 4 Toll-Like/agonistas
Receptor 4 Toll-Like/genética
Receptor 4 Toll-Like/metabolismo
beta-Arrestina 2/antagonistas & inibidores
beta-Arrestina 2/genética
beta-Arrestina 2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ARRB2 protein, human); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Antineoplastic Agents); 0 (IL1B protein, human); 0 (Interleukin-1beta); 0 (Ligands); 0 (Lipopolysaccharides); 0 (Neoplasm Proteins); 0 (Nerve Tissue Proteins); 0 (Opioid Peptides); 0 (Receptors, Opioid); 0 (TLR4 protein, human); 0 (TNF Receptor-Associated Factor 6); 0 (Tifab protein, human); 0 (Toll-Like Receptor 4); 0 (beta-Arrestin 2); 0 (lipopolysaccharide, Escherichia coli O111 B4); 0 (nociceptin receptor); 7AYI9N34FF (nociceptin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE


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[PMID]:28554003
[Au] Autor:Wang Y; Gupta M; Poonawala T; Farooqui M; Li Y; Peng F; Rao S; Ansonoff M; Pintar JE; Gupta K
[Ad] Endereço:Vascular Biology Center, Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minn.
[Ti] Título:Opioids and opioid receptors orchestrate wound repair.
[So] Source:Transl Res;185:13-23, 2017 Jul.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have previously shown that topical opioids including morphine and its congeners promote healing of full thickness ischemic wounds in rats. We examined the contribution of mu opioid receptor (MOPr)-mediated healing of full thickness ischemic wounds using MOPr and delta or kappa opioid receptor knockout (KO) mice. Wound closure in the early (day 5) as well as later phases was delayed in topical morphine or PBS-treated MOPr-KO mice compared with reciprocal treatments of wounds in wild-type (WT) mice. MOPr expression was significantly upregulated at 30 min in the wound margins and colocalized with wound margins and vasculature in the epidermal and dermal layers of the skin. We next examined whether neuropeptide expression was involved in the mechanism of MOPr-mediated wound closure. Substance P (SP) and calcitonin gene-related peptide immunoreactivity (ir) was significantly increased in the skin of MOPr-KO mice as compared with WT mice. Neuropeptide-ir was increased significantly in PBS-treated wounds of MOPr and WT mice, but morphine treatment reduced neuropeptide immunoreactivity in both as compared with PBS. Wounding of keratinocytes led to the release of opioid peptide beta-endorphin (ß-END) in conditioned medium, which stimulated the proliferation of endothelial cells. MOPr-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, CTOP) and nonselective OPr antagonist naloxone-inhibited endothelial proliferation induced by wounded keratinocyte-conditioned medium. In addition, accelerated wound area closure in vitro by morphine was suppressed by methylnaltrexone, a nonselective OPr antagonist with high affinity for MOPr. Morphine and its congeners stimulated the proliferation of endothelial cells from WT mice but not those from MOPr-KO mice. Furthermore, morphine-induced mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation in endothelial cells was significantly decreased in MOPr-KO mice as compared with WT mice. Collectively, these data suggest that MOPr plays a critical role in the proliferation phase with the formation of granulation tissue during wound healing.
[Mh] Termos MeSH primário: Analgésicos Opioides/uso terapêutico
Isquemia/patologia
Morfina/uso terapêutico
Receptores Opioides/metabolismo
Cicatrização/fisiologia
[Mh] Termos MeSH secundário: Administração Tópica
Analgésicos Opioides/administração & dosagem
Animais
Regulação da Expressão Gênica/fisiologia
Seres Humanos
Queratinócitos/efeitos dos fármacos
Camundongos
Camundongos Knockout
Morfina/administração & dosagem
Receptores Opioides/genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Receptors, Opioid); 76I7G6D29C (Morphine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE


  8 / 12476 MEDLINE  
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[PMID]:28535569
[Au] Autor:McRoberts PW; Pope JE; Apostol C
[Ad] Endereço:Holy Cross Hospital, Dept. of Pain Medicine, Fort Lauderdale, FL.
[Ti] Título:Reinstituting the Bolus - New Reasoning for an Existing Technique.
[So] Source:Pain Physician;20(4):E601-E603, 2017 May.
[Is] ISSN:2150-1149
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Improved intrathecal (IT) pump technology is increasing the accuracy of IT opioid bolus dosing and promising advances in pain therapy. Opioid bolus dosing can be used with a minimal continuous infusion or it can function as the sole therapy. Bolus-only dosing is characterized by minimal use of opioid (often less than 1 mg of IT morphine). It achieves adequate pain control while reducing tolerance and possibly opioid-induced hyperalgesia. It may prevent receptor saturation, and provide a "washing out" of the opioid receptor that prevents the observed dose escalation resulting from continuous infusions. With new bolus dosing possibilities, IT pumps can be used earlier in the treatment algorithm instead of being a late-stage treatment for patients who responded poorly to conservative treatments. We hypothesize that morphine bolus-only IT dosing will have comparable adverse effect rates, and possibly increased safety as compared to the more conservative continuous delivery method. We further predict that bolus-only delivery will provide better therapy satisfaction, improved functional scores, lower 24 hour opioid dose, and less dose escalation.
[Mh] Termos MeSH primário: Analgésicos Opioides/administração & dosagem
Injeções Espinhais
Morfina/administração & dosagem
Dor/tratamento farmacológico
[Mh] Termos MeSH secundário: Analgésicos Opioides/farmacocinética
Líquido Cefalorraquidiano/fisiologia
Relação Dose-Resposta a Droga
Seres Humanos
Morfina/farmacocinética
Receptores Opioides/efeitos dos fármacos
Receptores Opioides/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Receptors, Opioid); 76I7G6D29C (Morphine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE


  9 / 12476 MEDLINE  
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[PMID]:28388416
[Au] Autor:Lobingier BT; Hüttenhain R; Eichel K; Miller KB; Ting AY; von Zastrow M; Krogan NJ
[Ad] Endereço:Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
[Ti] Título:An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells.
[So] Source:Cell;169(2):350-360.e12, 2017 Apr 06.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation.
[Mh] Termos MeSH primário: Ascorbato Peroxidases/química
Mapas de Interação de Proteínas
Coloração e Rotulagem/métodos
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Lisossomos/metabolismo
Transporte Proteico
Receptores Acoplados a Proteínas-G/metabolismo
Receptores Opioides/metabolismo
Ubiquitina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Receptors, Opioid); 0 (Ubiquitin); EC 1.11.1.11 (Ascorbate Peroxidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE


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[PMID]:28314512
[Au] Autor:Truong PM; Hassan SA; Lee YS; Kopajtic TA; Katz JL; Chadderdon AM; Traynor JR; Deschamps JR; Jacobson AE; Rice KC
[Ad] Endereço:Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center
[Ti] Título:Modulation of opioid receptor affinity and efficacy via N-substitution of 9ß-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.
[So] Source:Bioorg Med Chem;25(8):2406-2422, 2017 Apr 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9ß-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K CO to improve the original N-demethylation procedure. Their binding affinity to the µ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTP S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the µ-opioid receptor (e.g., 1R,5R,9S-16: Ki=0.073, 0.74, and 1.99nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy µ-agonists (EC =0.74 and 18.5nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTP S assay. The enantiomer of 1R,5R,9S-16, (+)-1S,5S,9R-16 was unusual, it had good affinity for the µ-OR (Ki=26.5nM) and was an efficacious µ-antagonist (Ke=29.1nM). Molecular dynamics simulations of the µ-OR were carried out with the 1R,5R,9S-16 µ-agonist and the previously synthesized (1R,5R,9S)-(-)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(-)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9ß-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.
[Mh] Termos MeSH primário: Simulação por Computador
Morfinanos/síntese química
Morfinanos/farmacologia
Receptores Opioides/efeitos dos fármacos
[Mh] Termos MeSH secundário: Espectroscopia de Ressonância Magnética Nuclear de Carbono-13
Cristalografia por Raios X
Modelos Moleculares
Simulação de Dinâmica Molecular
Morfinanos/química
Morfinanos/metabolismo
Ligação Proteica
Espectroscopia de Prótons por Ressonância Magnética
Receptores Opioides/metabolismo
Espectrometria de Massas por Ionização por Electrospray
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Morphinans); 0 (Receptors, Opioid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170319
[St] Status:MEDLINE



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