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[PMID]:29199977
[Au] Autor:Xu S; Long BN; Boris GH; Chen A; Ni S; Kennedy MA
[Ad] Endereço:Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
[Ti] Título:Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 12):970-984, 2017 Dec 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:K-Ras, a molecular switch that regulates cell growth, apoptosis and metabolism, is activated when it undergoes a conformation change upon binding GTP and is deactivated following the hydrolysis of GTP to GDP. Hydrolysis of GTP in water is accelerated by coordination to K-Ras, where GTP adopts a high-energy conformation approaching the transition state. The G12A mutation reduces intrinsic K-Ras GTP hydrolysis by an unexplained mechanism. Here, crystal structures of G12A K-Ras in complex with GDP, GTP, GTPγS and GppNHp, and of Q61A K-Ras in complex with GDP, are reported. In the G12A K-Ras-GTP complex, the switch I region undergoes a significant reorganization such that the Tyr32 side chain points towards the GTP-binding pocket and forms a hydrogen bond to the GTP γ-phosphate, effectively stabilizing GTP in its precatalytic state, increasing the activation energy required to reach the transition state and contributing to the reduced intrinsic GTPase activity of G12A K-Ras mutants.
[Mh] Termos MeSH primário: Guanosina 5´-O-(3-Tiotrifosfato)/metabolismo
Guanosina Difosfato/metabolismo
Guanosina Trifosfato/metabolismo
Conformação Proteica
Proteínas Proto-Oncogênicas p21(ras)/química
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalografia por Raios X
Seres Humanos
Ligações de Hidrogênio
Hidrólise
Modelos Moleculares
Mutação
Proteínas Proto-Oncogênicas p21(ras)/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); 146-91-8 (Guanosine Diphosphate); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); 86-01-1 (Guanosine Triphosphate); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317015418


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[PMID]:29211764
[Au] Autor:Schober DA; Croy CH; Ruble CL; Tao R; Felder CC
[Ad] Endereço:Neuroscience, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
[Ti] Título:Identification, expression and functional characterization of M4L, a muscarinic acetylcholine M4 receptor splice variant.
[So] Source:PLoS One;12(12):e0188330, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rodent genomic alignment sequences support a 2-exon model for muscarinic M4 receptor. Using this model a novel N-terminal extension was discovered in the human muscarinic acetylcholine M4 receptor. An open reading frame was discovered in the human, mouse and rat with a common ATG (methionine start codon) that extended the N-terminus of the muscarinic acetylcholine M4 receptor subtype by 155 amino acids resulting in a longer variant. Transcriptional evidence for this splice variant was confirmed by RNA-Seq and RT-PCR experiments performed from human donor brain prefrontal cortices. We detected a human upstream exon indicating the translation of the mature longer M4 receptor transcript. The predicted size for the longer two-exon M4 receptor splice variant with the additional 155 amino acid N-terminal extension, designated M4L is 69.7 kDa compared to the 53 kDa canonical single exon M4 receptor (M4S). Western blot analysis from a mammalian overexpression system, and saturation radioligand binding with [3H]-NMS (N-methyl-scopolamine) demonstrated the expression of this new splice variant. Comparative pharmacological characterization between the M4L and M4S receptors revealed that both the orthosteric and allosteric binding sites for both receptors were very similar despite the addition of an N-terminal extension.
[Mh] Termos MeSH primário: Processamento de RNA
Receptor Muscarínico M4/metabolismo
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Sítios de Ligação
Ligação Competitiva
Éxons
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Seres Humanos
Camundongos
Reação em Cadeia da Polimerase
Córtex Pré-Frontal/metabolismo
Ensaio Radioligante
Ratos
Receptor Muscarínico M4/genética
Análise de Sequência de RNA
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Muscarinic M4); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188330


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[PMID]:28822840
[Au] Autor:Chakraborti S; Sarkar J; Chowdhury A; Chakraborti T
[Ad] Endereço:Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India. Electronic address: sajal_chakraborti@yahoo.com.
[Ti] Título:Role of ADP ribosylation factor6- Cytohesin1-PhospholipaseD signaling axis in U46619 induced activation of NADPH oxidase in pulmonary artery smooth muscle cell membrane.
[So] Source:Arch Biochem Biophys;633:1-14, 2017 Nov 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Treatment of human pulmonary artery smooth muscle cells (HPASMCs) with the thromboxane A2 receptor antagonist, SQ29548 inhibited U46619 stimulation of phospholipase D (PLD) and NADPH oxidase activities in the cell membrane. Pretreatment with apocynin inhibited U46619 induced increase in NADPH oxidase activity. The cell membrane contains predominantly PLD2 along with PLD1 isoforms of PLD. Pretreatment with pharmacological and genetic inhibitors of PLD2, but not PLD1, attenuated U46619 stimulation of NADPH oxidase activity. U46619 stimulation of PLD and NADPH oxidase activities were insensitive to BFA and Clostridium botulinum C3 toxin; however, pretreatment with secinH3 inhibited U46619 induced increase in PLD and NADPH oxidase activities suggesting a major role of cytohesin in U46619-induced increase in PLD and NADPH oxidase activities. Arf-1, Arf-6, cytohesin-1 and cytohesin-2 were observed in the cytosolic fraction, but only Arf-6 and cytohesin-1 were translocated to the cell membrane upon treatment with U46619. Coimmunoprecipitation study showed association of Arf-6 with cytohesin-1 in the cell membrane fraction. In vitro binding of GTPγS with Arf-6 required the presence of cytohesin-1 and that occurs in BFA insensitive manner. Overall, BFA insensitive Arf6-cytohesin1 signaling axis plays a pivotal role in U46619-mediated activation of PLD leading to stimulation of NADPH oxidase activity in HPASMCs.
[Mh] Termos MeSH primário: Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia
Fatores de Ribosilação do ADP/genética
Fatores de Troca do Nucleotídeo Guanina/genética
NADPH Oxidases/genética
Fosfolipase D/genética
Vasoconstritores/farmacologia
[Mh] Termos MeSH secundário: ADP Ribose Transferases/farmacologia
Fatores de Ribosilação do ADP/metabolismo
Acetofenonas/farmacologia
Antioxidantes/farmacologia
Toxinas Botulínicas/farmacologia
Brefeldina A/farmacologia
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Proteínas Ativadoras de GTPase/antagonistas & inibidores
Proteínas Ativadoras de GTPase/genética
Proteínas Ativadoras de GTPase/metabolismo
Regulação da Expressão Gênica
Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia
Seres Humanos
Hidrazinas/farmacologia
Miócitos de Músculo Liso/citologia
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
NADPH Oxidases/metabolismo
Fosfolipase D/antagonistas & inibidores
Fosfolipase D/metabolismo
Cultura Primária de Células
Inibidores da Síntese de Proteínas/farmacologia
Artéria Pulmonar/citologia
Artéria Pulmonar/efeitos dos fármacos
Artéria Pulmonar/metabolismo
Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores
Receptores de Tromboxano A2 e Prostaglandina H2/genética
Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo
Transdução de Sinais
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetophenones); 0 (Antioxidants); 0 (GTPase-Activating Proteins); 0 (Guanine Nucleotide Exchange Factors); 0 (Hydrazines); 0 (Protein Synthesis Inhibitors); 0 (Receptors, Thromboxane A2, Prostaglandin H2); 0 (SecinH3); 0 (Triazoles); 0 (Vasoconstrictor Agents); 0 (cytohesin-1); 0 (cytohesin-2); 20350-15-6 (Brefeldin A); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); 76898-47-0 (15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid); 98299-61-7 (SQ 29548); B6J7B9UDTR (acetovanillone); EC 1.6.3.- (NADPH Oxidases); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.- (exoenzyme C3, Clostridium botulinum); EC 3.1.4.- (phospholipase D2); EC 3.1.4.4 (Phospholipase D); EC 3.1.4.4 (phospholipase D1); EC 3.4.24.69 (Botulinum Toxins); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ADP-ribosylation factor 6)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170821
[St] Status:MEDLINE


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[PMID]:28792219
[Au] Autor:Nguyen T; German N; Decker AM; Langston TL; Gamage TF; Farquhar CE; Li JX; Wiley JL; Thomas BF; Zhang Y
[Ad] Endereço:Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
[Ti] Título:Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution.
[So] Source:J Med Chem;60(17):7410-7424, 2017 Sep 14.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (2). Similar to 2, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [ S]GTP-γ-S binding while enhancing [ H]CP55,940 binding to the CB1 receptor. Structure-activity relationship studies revealed that the pyridinyl ring of 2 could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. 34 (RTICBM-74) had similar potencies as 2 in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, 34 was more effective than 2 in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction.
[Mh] Termos MeSH primário: Regulação Alostérica/efeitos dos fármacos
Compostos de Fenilureia/química
Compostos de Fenilureia/farmacologia
Piridinas/química
Piridinas/farmacologia
Receptor CB1 de Canabinoide/metabolismo
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Linhagem Celular
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Seres Humanos
Microssomos Hepáticos/metabolismo
Compostos de Fenilureia/metabolismo
Piridinas/metabolismo
Pirrolidinas/química
Pirrolidinas/metabolismo
Pirrolidinas/farmacologia
Ratos
Receptor CB1 de Canabinoide/agonistas
Receptor CB1 de Canabinoide/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-chlorophenyl)-3-(3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl)urea); 0 (Phenylurea Compounds); 0 (Pyridines); 0 (Pyrrolidines); 0 (Receptor, Cannabinoid, CB1); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); SY7Q814VUP (Calcium)
[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:170810
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00707


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[PMID]:28504339
[Au] Autor:Matus-Ortega ME; Leff Gelman P; Calva-Nieves JC; Flores-Zamora A; Salazar-Juárez A; Torner-Aguilar CA; Gamba G; De Los Heros P; Peng B; Pintar JE; Gompf HS; Allen CN; Antón-Palma B
[Ad] Endereço:Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, México.
[Ti] Título:Mexneurin is a novel precursor of peptides in the central nervous system of rodents.
[So] Source:FEBS Lett;591(12):1627-1636, 2017 Jun.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Endomorphins (EMs) have been proposed as the endogenous ligand agonists of the µ-opioid receptor; however, no propeptide precursor protein for EMs has been identified. Here, to identify the presumed precursor of EMs, we designed an immunoscreening assay using specific affinity-purified rabbit antisera raised against synthetic EMs in a whole-mouse brain cDNA library. Following this approach, we identify a DNA sequence encoding a protein precursor, which we name proMexneurin, that contains three different peptide sequences: Mexneurin-1 (an EM-like peptide), Mexneurin-2, and Mexneurin-3, a peptide which appears to be unrelated to EMs. RT-PCR analysis and in situ hybridization reveal a widespread distribution of proMexneurin mRNA throughout the mouse brain. Both Mexneurin-1 and Mexneurin-3 peptides display biological activities in the mouse CNS.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Neurônios/metabolismo
Proteínas Nucleares/metabolismo
Precursores de Proteínas/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sequência de Bases
Encéfalo/citologia
Encéfalo/fisiologia
Potenciais Evocados
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Hipocampo/citologia
Hipocampo/metabolismo
Hipocampo/fisiologia
Ligantes
Masculino
Camundongos Endogâmicos BALB C
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Neurônios/citologia
Neurônios/fisiologia
Proteínas Nucleares/química
Proteínas Nucleares/genética
Fases de Leitura Aberta
Técnicas de Patch-Clamp
Precursores de Proteínas/química
Precursores de Proteínas/genética
Processamento de Proteína Pós-Traducional
Proteólise
RNA Mensageiro/metabolismo
Ratos Sprague-Dawley
Ratos Wistar
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Nerve Tissue Proteins); 0 (Nuclear Proteins); 0 (Protein Precursors); 0 (RNA, Messenger); 0 (Trnp1 protein, mouse); 0 (mexneurin-2, mouse); 0 (mexneurin-3, mouse); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
[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:170516
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12679


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[PMID]:28319053
[Au] Autor:Xu J; Lu Z; Narayan A; Le Rouzic VP; Xu M; Hunkele A; Brown TG; Hoefer WF; Rossi GC; Rice RC; Martínez-Rivera A; Rajadhyaksha AM; Cartegni L; Bassoni DL; Pasternak GW; Pan YX
[Ti] Título:Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine.
[So] Source:J Clin Invest;127(4):1561-1573, 2017 Apr 03.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Extensive 3' alternative splicing of the mu opioid receptor gene OPRM1 creates multiple C-terminal splice variants. However, their behavioral relevance remains unknown. The present study generated 3 mutant mouse models with truncated C termini in 2 different mouse strains, C57BL/6J (B6) and 129/SvEv (129). One mouse truncated all C termini downstream of Oprm1 exon 3 (mE3M mice), while the other two selectively truncated C-terminal tails encoded by either exon 4 (mE4M mice) or exon 7 (mE7M mice). Studies of these mice revealed divergent roles for the C termini in morphine-induced behaviors, highlighting the importance of C-terminal variants in complex morphine actions. In mE7M-B6 mice, the exon 7-associated truncation diminished morphine tolerance and reward without altering physical dependence, whereas the exon 4-associated truncation in mE4M-B6 mice facilitated morphine tolerance and reduced morphine dependence without affecting morphine reward. mE7M-B6 mutant mice lost morphine-induced receptor desensitization in the brain stem and hypothalamus, consistent with exon 7 involvement in morphine tolerance. In cell-based studies, exon 7-associated variants shifted the bias of several mu opioids toward ß-arrestin 2 over G protein activation compared with the exon 4-associated variant, suggesting an interaction of exon 7-associated C-terminal tails with ß-arrestin 2 in morphine-induced desensitization and tolerance. Together, the differential effects of C-terminal truncation illustrate the pharmacological importance of OPRM1 3' alternative splicing.
[Mh] Termos MeSH primário: Analgésicos Opioides/farmacologia
Morfina/farmacologia
Receptores Opioides mu/metabolismo
[Mh] Termos MeSH secundário: Processamento Alternativo
Animais
Encéfalo/metabolismo
Códon sem Sentido
Relação Dose-Resposta a Droga
Tolerância a Medicamentos
Éxons
Trânsito Gastrointestinal/efeitos dos fármacos
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Locomoção/efeitos dos fármacos
Masculino
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Dependência de Morfina/genética
Ligação Proteica
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Receptores Opioides mu/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Codon, Nonsense); 0 (Oprm protein, mouse); 0 (Protein Isoforms); 0 (Receptors, Opioid, mu); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); 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:170321
[St] Status:MEDLINE


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[PMID]:28282254
[Au] Autor:Trans DJ; Bai R; Addison JB; Liu R; Hamel E; Coleman MA; Henderson PT
[Ad] Endereço:a Department of Internal Medicine and UC Davis Comprehensive Cancer Center , University of California , Davis , CA , USA.
[Ti] Título:Synthesis of two fluorescent GTPγS molecules and their biological relevance.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(6):379-391, 2017 Jun 03.
[Is] ISSN:1532-2335
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fluorescent GTP analogues are utilized for an assortment of nucleic acid and protein characterization studies. Non-hydrolysable analogues such as GTPγS offer the advantage of keeping proteins in a GTP-bound conformation due to their resistance to hydrolysis into GDP. Two novel fluorescent GTPγS molecules were developed by linking fluorescein and tetramethylrhodamine to the γ-thiophosphate of GTPγS. Chemical and biological analysis of these two compounds revealed their successful synthesis and ability to bind to the nucleotide-binding site of tubulin. These two new fluorescent non-hydrolysable nucleotides offer new possibilities for biophysical and biochemical characterization of GTP-binding proteins.
[Mh] Termos MeSH primário: Corantes Fluorescentes/síntese química
Guanosina 5´-O-(3-Tiotrifosfato)/síntese química
[Mh] Termos MeSH secundário: Técnicas de Química Sintética
Transferência de Energia
Corantes Fluorescentes/metabolismo
Proteínas de Ligação ao GTP/metabolismo
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Multimerização Proteica
Estrutura Quaternária de Proteína
Tubulina (Proteína)/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (Tubulin); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); EC 3.6.1.- (GTP-Binding Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2016.1231320


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[PMID]:28088085
[Au] Autor:Ragusa G; Gómez-Cañas M; Morales P; Rodríguez-Cueto C; Pazos MR; Asproni B; Cichero E; Fossa P; Pinna GA; Jagerovic N; Fernández-Ruiz J; Murineddu G
[Ad] Endereço:Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy.
[Ti] Título:New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking.
[So] Source:Eur J Med Chem;127:398-412, 2017 Feb 15.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:In the last few years, cannabinoid type-2 receptor (CB R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCB R and hCB R. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB -affinity (K CB = 2.0 ± 0.81 nM) and a notable selectivity (K CB /K CB > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CB R inverse agonists in [ S]-GTPγS binding assay. ADME predictions of the newly synthesized CB R ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CB R ligands.
[Mh] Termos MeSH primário: Agonistas de Receptores de Canabinoides/química
Agonistas de Receptores de Canabinoides/farmacologia
Agonismo Inverso de Drogas
Simulação de Acoplamento Molecular
Piridazinas/química
Piridazinas/farmacologia
Receptor CB2 de Canabinoide/metabolismo
[Mh] Termos MeSH secundário: Agonistas de Receptores de Canabinoides/síntese química
Agonistas de Receptores de Canabinoides/metabolismo
Técnicas de Química Sintética
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Células HEK293
Seres Humanos
Conformação Proteica
Piridazinas/síntese química
Piridazinas/metabolismo
Receptor CB2 de Canabinoide/agonistas
Receptor CB2 de Canabinoide/antagonistas & inibidores
Receptor CB2 de Canabinoide/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cannabinoid Receptor Agonists); 0 (Pyridazines); 0 (Receptor, Cannabinoid, CB2); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170228
[Lr] Data última revisão:
170228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170115
[St] Status:MEDLINE


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[PMID]:27996211
[Au] Autor:Wang JR; Sun PH; Ren ZX; Meltzer HY; Zhen XC
[Ad] Endereço:Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University, Suzhou, Jiangsu, China.
[Ti] Título:GSK-3ß Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia.
[So] Source:CNS Neurosci Ther;23(2):174-187, 2017 Feb.
[Is] ISSN:1755-5949
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function. AIMS: To investigate the physical interaction and functional modulation between D1R and GSK-3ß. RESULTS: D1R and GSK-3ß physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C-terminus of D1R. Inhibition of GSK-3ß impaired D1R activation along with a decrease in D1R-GSK-3ß interaction. GSK-3ß inhibition reduced agonist-stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of ß-arrestin-2. Similarly, inhibition of GSK-3ß in rat PFC also resulted in impaired D1R activation and association with GSK-3ß. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK-3ß activity and D1R-GSK-3ß association and decreased D1R activation in the PFC. CONCLUSIONS: The present work identified GSK-3ß as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK-3ß-regulated D1R function which may underlie D1R dysfunction in schizophrenia.
[Mh] Termos MeSH primário: Glicogênio Sintase Quinase 3 beta/metabolismo
Córtex Pré-Frontal/metabolismo
Receptores de Dopamina D1/metabolismo
Esquizofrenia/metabolismo
Esquizofrenia/patologia
[Mh] Termos MeSH secundário: Adjuvantes Imunológicos/farmacologia
Animais
AMP Cíclico/metabolismo
Modelos Animais de Doenças
Agonistas de Dopamina/farmacologia
Endocitose/efeitos dos fármacos
Endocitose/genética
Inibidores Enzimáticos/farmacologia
Fenoldopam/farmacologia
Glicogênio Sintase Quinase 3 beta/genética
Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética
Células HEK293
Seres Humanos
Indóis/farmacologia
Cloreto de Lítio/farmacologia
Maleimidas/farmacologia
Córtex Pré-Frontal/efeitos dos fármacos
Transporte Proteico/efeitos dos fármacos
Ratos
Esquizofrenia/induzido quimicamente
beta-Arrestinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adjuvants, Immunologic); 0 (Dopamine Agonists); 0 (Enzyme Inhibitors); 0 (Indoles); 0 (Maleimides); 0 (Receptors, Dopamine D1); 0 (SB 216763); 0 (beta-Arrestins); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); E0399OZS9N (Cyclic AMP); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); G4962QA067 (Lithium Chloride); INU8H2KAWG (Fenoldopam)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161221
[St] Status:MEDLINE
[do] DOI:10.1111/cns.12664


  10 / 5474 MEDLINE  
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[PMID]:27984018
[Au] Autor:Jafurulla M; Bandari S; Pucadyil TJ; Chattopadhyay A
[Ad] Endereço:CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
[Ti] Título:Sphingolipids modulate the function of human serotonin receptors: Insights from sphingolipid-deficient cells.
[So] Source:Biochim Biophys Acta;1859(4):598-604, 2017 04.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Sphingolipids are essential components of eukaryotic cell membranes and are known to modulate a variety of cellular functions. It is becoming increasingly clear that membrane lipids play a crucial role in modulating the function of integral membrane proteins such as G protein-coupled receptors (GPCRs). In this work, we utilized LY-B cells, that are sphingolipid-auxotrophic mutants defective in sphingolipid biosynthesis, to monitor the role of cellular sphingolipids in the function of an important neurotransmitter receptor, the serotonin receptor. Serotonin receptors belong to the family of GPCRs and are implicated in behavior, development and cognition. Our results show that specific ligand binding and G-protein coupling of the serotonin receptor exhibit significant enhancement under sphingolipid-depleted conditions, which reversed to control levels upon replenishment of cellular sphingolipids. In view of the reported role of sphingolipids in neuronal metabolism and pathogenesis of several neuropsychiatric disorders, exploring the role of serotonin receptors under conditions of defective sphingolipid metabolism assumes relevance, and could contribute to our overall understanding of such neuropsychiatric disorders. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
[Mh] Termos MeSH primário: 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia
Membrana Celular/efeitos dos fármacos
Receptor 5-HT1A de Serotonina/genética
Agonistas de Receptores 5-HT1 de Serotonina/farmacologia
Esfingosina/metabolismo
[Mh] Termos MeSH secundário: 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo
Animais
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Células CHO
Membrana Celular/metabolismo
Cricetulus
Deleção de Genes
Regulação da Expressão Gênica
Genes Reporter
Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo
Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia
Seres Humanos
Cinética
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Lipídeos de Membrana/metabolismo
Receptor 5-HT1A de Serotonina/metabolismo
Serina C-Palmitoiltransferase/deficiência
Serina C-Palmitoiltransferase/genética
Agonistas de Receptores 5-HT1 de Serotonina/metabolismo
Transdução de Sinais
Esfingosina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Luminescent Proteins); 0 (Membrane Lipids); 0 (Serotonin 5-HT1 Receptor Agonists); 0 (yellow fluorescent protein, Bacteria); 112692-38-3 (Receptor, Serotonin, 5-HT1A); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); 78950-78-4 (8-Hydroxy-2-(di-n-propylamino)tetralin); EC 2.3.1.50 (Serine C-Palmitoyltransferase); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE



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