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1.
Rinsho Ketsueki ; 60(9): 1108-1119, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597834

RESUMO

Conventional chemotherapy with cytarabine and anthracycline (often referred to as "7+3") has been used for many years in the treatment of acute myeloid leukemia (AML). Despite meaningful advances in areas of supportive care and transplantation, little progress has been made in developing new chemotherapy options. In 2018, The Food and Drug Administration (FDA) of the US approved several novel agents for AML treatment as follows: ivosidenib, an inhibitor of isocitrate dehydrogenase-1; venetoclax, a potent inhibitor of bcl2; and glasdegib, an inhibitor of hedgehog signaling pathway. Moreover, clinical trials of alvocidib (flavopiridol), an inhibitor of the CDK9, pevonedistat, an inhibitor of NEDD8, and APR-246, a reactivator of mutant p53, are in progress. These agents will either be incorporated into the conventional 7+3 regimen or combined with hypomethylating agents to improve the outcome of AML therapy, and the results will guide the next stage of precision medicine in the treatment of AML.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Benzimidazóis/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ciclopentanos/farmacologia , Aprovação de Drogas , Flavonoides/farmacologia , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Terapia de Alvo Molecular , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
2.
Expert Opin Drug Metab Toxicol ; 15(10): 849-867, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31566028

RESUMO

Introduction: Piperine, the major bioactive component from black pepper, has gained increasing attention for its beneficial effects in the central nervous system (CNS). However, its related pharmacodynamics and brain pharmacokinetics, as well as its interaction with other CNS drugs are lacking, which may hinder its therapeutic and safe use. Areas covered: The current review provides an updated summary on CNS activities of piperine, including anti-epileptic, anti-depressive and neurodegeneration protection effect. The brain pharmacokinetic properties of piperine together with the approaches to enhance its aqueous solubility were summarized. Considering the wide use of black pepper and the well-reported alteration on CYP and transporters by piperine, interactions between piperine and CNS drugs are also illustrated for the first time. Expert opinion: Although the CNS beneficial effects of piperine have been extensively studied in preclinical models, clinical evidence on its CNS application is barely available, which may be attributed to its limited aqueous solubility, unclear pharmacokinetic properties in humans and potential toxicities during long-term use at higher doses. Although beneficial interactions between piperine and certain CNS drugs were often reported in preclinical studies, more mechanistic studies with clinically relevant doses should be conducted to provide guidance on their clinical combination use.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacocinética , Animais , Benzodioxóis/isolamento & purificação , Benzodioxóis/farmacocinética , Fármacos do Sistema Nervoso Central/isolamento & purificação , Fármacos do Sistema Nervoso Central/farmacocinética , Fármacos do Sistema Nervoso Central/farmacologia , Doenças do Sistema Nervoso Central/fisiopatologia , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Piperidinas/isolamento & purificação , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/isolamento & purificação , Alcamidas Poli-Insaturadas/farmacocinética
3.
Eur J Med Chem ; 179: 680-693, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280020

RESUMO

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ±â€¯0.07 µM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ±â€¯1.25 and 5.94 ±â€¯1.08 µM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Piperidinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Cavalos , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
4.
Nat Neurosci ; 22(8): 1223-1234, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332372

RESUMO

Social deficit is a core clinical feature of autism spectrum disorder (ASD) but the underlying neural mechanisms remain largely unclear. We demonstrate that structural and functional impairments occur in glutamatergic synapses in the pyramidal neurons of the anterior cingulate cortex (ACC) in mice with a mutation in Shank3, a high-confidence candidate ASD gene. Conditional knockout of Shank3 in the ACC was sufficient to generate excitatory synaptic dysfunction and social interaction deficits, whereas selective enhancement of ACC activity, restoration of SHANK3 expression in the ACC, or systemic administration of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-positive modulator improved social behavior in Shank3 mutant mice. Our findings provide direct evidence for the notion that the ACC has a role in the regulation of social behavior in mice and indicate that ACC dysfunction may be involved in social impairments in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Giro do Cíngulo/patologia , Proteínas do Tecido Nervoso/genética , Comportamento Social , Animais , Dioxóis/farmacologia , Modelos Animais de Doenças , Ácido Glutâmico , Asseio Animal , Giro do Cíngulo/fisiopatologia , Relações Interpessoais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Optogenética , Piperidinas/farmacologia , Células Piramidais/patologia , Receptores de AMPA/agonistas , Sinapses/patologia
5.
Eur J Med Chem ; 179: 358-375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260890

RESUMO

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 µM and 10.71 µM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Células A549 , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/química , Relação Estrutura-Atividade
6.
Anticancer Res ; 39(7): 3579-3584, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262882

RESUMO

BACKGROUND/AIM: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. MATERIALS AND METHODS: Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. RESULTS: Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. CONCLUSION: Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vorinostat/farmacologia , Quinase do Linfoma Anaplásico/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo
7.
Cell Physiol Biochem ; 53(1): 186-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278696

RESUMO

BACKGROUND/AIMS: Estrogen could play a key role in the mechanisms underlying sex-related disparity in the incidence of thrombotic events. We investigated whether estrogen receptors (ERs) were expressed in human red blood cells (RBCs), and if they affected cell signaling of erythrocyte constitutive isoform of endothelial NO-synthase (eNOS) and nitric oxide (NO) release. METHODS: RBCs from 29 non-smoker volunteers (15 males and 14 females) aged between 20 and 40 years were analyzed by cytometry and western blot. In particular, content and distribution of ER-α and ER-ß, tyrosine kinases and eNOS phosphorylation and NO release were analyzed. RESULTS: We demonstrated that: i) both ER-α and ER-ß were expressed by RBCs; ii) they were both functionally active; and iii) ERs distribution and function were different in males and females. In particular, ERs modulated eNOS phosphorylation and NO release in RBCs from both sexes, but they induced the phosphorylation of specific tyrosine residues of kinases linked to eNOS activation and NO release in the RBCs from females only. CONCLUSION: Collectively, these data suggest that ERs could play a critical role in RBC intracellular signaling. The possible implication of this signaling in sex-linked risk disparity in human cardiovascular diseases, e.g. in thrombotic events, may not be ruled out.


Assuntos
Receptores Estrogênicos/metabolismo , Transdução de Sinais , Adulto , Dronabinol/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
8.
Planta Med ; 85(13): 1114-1123, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31340396

RESUMO

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.


Assuntos
Alcaloides/uso terapêutico , Benzodioxóis/uso terapêutico , Capsaicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/metabolismo , Veículos Farmacêuticos/uso terapêutico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Alcaloides/farmacologia , Animais , Benzodioxóis/farmacologia , Capsaicina/farmacologia , Mucosa Nasal/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Ovinos
9.
RNA ; 25(9): 1078-1090, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31164480

RESUMO

RNAi mediated by small-interfering RNAs (siRNAs) operates via transcriptional (TGS) and posttranscriptional gene silencing (PTGS). In Arabidopsis thaliana, TGS relies on DICER-LIKE-3 (DCL3)-dependent 24-nt siRNAs loaded into AGO4-clade ARGONAUTE effector proteins. PTGS operates via DCL4-dependent 21-nt siRNAs loaded into AGO1-clade proteins. We set up and validated a medium-throughput, semi-automatized procedure enabling chemical screening, in a 96-well in vitro format, of Arabidopsis transgenic seedlings expressing an inverted-repeat construct from the phloem companion cells. The ensuing quantitative PTGS phenotype was exploited to identify molecules, which, upon topical application, either inhibit or enhance siRNA biogenesis/activities. The vast majority of identified modifiers were enhancers, among which Sortin1, Isoxazolone, and [5-(3,4-dichlorophenyl)furan-2-yl]-piperidine-1-ylmethanethione (DFPM) provided the most robust and consistent results, including upon their application onto soil-grown plants in which their effect was nonautonomous and long lasting. The three molecules increased the RNAi potency of the inverted-repeat construct, in large part by enhancing 21-nt siRNA accumulation and loading into AGO1, and concomitantly reducing AGO4 and DCL3 levels in planta. A similar, albeit not identical effect, was observed on 22-nt siRNAs produced from a naturally occurring inverted-repeat locus, demonstrating that the molecules also enhance endogenous PTGS. In standardized assays conducted in seedling extracts, the three enhancers selectively increased DCL4-mediated processing of in vitro-synthesized double-stranded RNAs, indicating the targeting of a hitherto unknown PTGS component probably independent of the DCL4-cofactor DOUBLE-STRANDED RNA-BINDING 4 (DRB4). This study establishes the proof-of-concept that RNAi efficacy can be modulated by chemicals in a whole organism. Their potential applications and the associated future research are discussed.


Assuntos
Arabidopsis/genética , Indenos/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Interferência de RNA/efeitos dos fármacos , Tionas/farmacologia , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas Argonauta/genética , Avaliação Pré-Clínica de Medicamentos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Proteínas de Ligação a RNA/genética , Ribonuclease III/genética
10.
Neuron ; 103(3): 432-444.e3, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31221559

RESUMO

Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Potenciação de Longa Duração/fisiologia , Núcleo Accumbens/fisiologia , Substância P/metabolismo , Potenciais de Ação/fisiologia , Animais , Aprepitanto/farmacologia , Sinalização do Cálcio/fisiologia , Neurônios Colinérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/citologia , Estimulação Luminosa , Piperidinas/farmacologia , Receptor Muscarínico M1/fisiologia , Receptores de AMPA/fisiologia , Receptores de Dopamina D1/análise , Receptores de Dopamina D2/análise , Receptores da Neurocinina-1/fisiologia
11.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
12.
Expert Rev Clin Pharmacol ; 12(7): 681-691, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31159608

RESUMO

Introduction: Parkinson's disease psychosis (PDP) may affect up to 60% of patients with Parkinson's disease over the course of their disease, and is associated with poor prognosis, including increased risks of mortality and nursing home placement. PDP treatments have been limited to off-label use of atypical antipsychotics, most of which pose risks of worsened motor symptoms and other potential adverse events (AEs) due to their dopamine receptor blockade and additional off-target receptor affinities. Pimavanserin is a highly selective 5-HT2A inverse agonist and poses no known risks for worsening of parkinsonism or other off-target receptor AEs. Pimavanserin is the first and only medication approved for PDP treatment. Areas covered: This review covers estimated prevalence, clinical characteristics, diagnostic criteria, and risk factors for PDP; the hypothetical progression of PDP; management of PDP including use of antipsychotics; pharmacology and clinical trial data on pimavanserin; and expert opinion on PDP treatment. The NLM/PubMed database was searched for papers using the search terms of "PDP" AND "treatment" AND "pimavanserin" for the last 10 years. Expert opinion: The recent insights into PDP pathophysiology and approval of the only medication specifically to treat PDP are key advances that should improve the recognition, diagnosis, and management of PDP.


Assuntos
Doença de Parkinson/tratamento farmacológico , Piperidinas/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Ureia/análogos & derivados , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Progressão da Doença , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Piperidinas/farmacologia , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/fisiopatologia , Fatores de Risco , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Ureia/farmacologia , Ureia/uso terapêutico
13.
Expert Opin Ther Pat ; 29(7): 497-507, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31242055

RESUMO

INTRODUCTION: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research. AREAS COVERED: 2013-2018 patent literature on mGlu2 receptor PAMs. EXPERT OPINION: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.


Assuntos
Indóis/uso terapêutico , Oxidiazóis/uso terapêutico , Piperidinas/uso terapêutico , Piridonas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Humanos , Indóis/farmacologia , Oxidiazóis/farmacologia , Patentes como Assunto , Piperidinas/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
14.
Nat Commun ; 10(1): 2505, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175285

RESUMO

Brain signals that govern memory formation remain incompletely identified. The hypothalamus is implicated in memory disorders, but how its rapidly changing activity shapes memorization is unknown. During encounters with objects, hypothalamic melanin-concentrating hormone (MCH) neurons emit brief signals that reflect object novelty. Here we show that targeted optogenetic silencing of these signals, performed selectively during the initial object encounters (i.e. memory acquisition), prevents future recognition of the objects. We identify an upstream inhibitory microcircuit from hypothalamic GAD65 neurons to MCH neurons, which constrains the memory-promoting MCH cell bursts. Finally, we demonstrate that silencing the GAD65 cells during object memory acquisition improves future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that object-associated signals in genetically distinct but interconnected hypothalamic neurons differentially control whether the brain forms object memories. This gating of memory formation by hypothalamic activity establishes appropriate behavioral responses to novel and familiar objects.


Assuntos
Glutamato Descarboxilase/metabolismo , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/fisiologia , Melaninas/metabolismo , Memória/fisiologia , Neurônios/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Recognição (Psicologia)/fisiologia , Animais , Hipotálamo/citologia , Hipotálamo/metabolismo , Memória/efeitos dos fármacos , Camundongos , Inibição Neural/fisiologia , Vias Neurais , Optogenética , Piperidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Recognição (Psicologia)/efeitos dos fármacos
15.
Artigo em Chinês | MEDLINE | ID: mdl-31245954

RESUMO

OBJECTIVE: To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application. METHODS: Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR. RESULTS: Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P<0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P<0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P<0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P<0.05) in DM + H group (P<0.05). CONCLUSION: Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Piperidinas , Baço , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação , Insulina , Proteínas Substratos do Receptor de Insulina/efeitos dos fármacos , Masculino , Camundongos , Pâncreas , Piperidinas/farmacologia , Distribuição Aleatória , Receptor de Insulina/efeitos dos fármacos , Baço/efeitos dos fármacos
16.
Mol Carcinog ; 58(8): 1502-1511, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31045274

RESUMO

Glioblastoma (GBM) is one of the major causes of brain cancer-related mortality worldwide. Temozolomide (TMZ) is an important agent against GBM. Acquired TMZ-resistance severely limits the chemotherapeutic effect and leads to poor GBM patient survival. To study the underlying mechanism of drug resistance, two TMZ resistant GBM cell lines, A172 and U87, were generated. In this study, the TMZ resistant cells have less apoptosis and cell-cycle change in response to the TMZ treatment. Western blot results revealed that cyclin E1 was upregulation in TMZ resistant cells. Inhibition or depletion of cyclin E1 re-sensitized the resistant cells to the TMZ treatment, which indicated the induction of cyclin E1 is the cause of TMZ resistance in GBM cells. Furthermore, we also found the expression of cyclin E1 stabilized the expression of Mcl-1, which contributes to the TMZ resistance in GBM cells. Finally, our in vivo xenograft data showed that the combination of flavopiridol, a cyclin E1/CDK2 inhibitor, overcomes the TMZ resistant by inducing higher apoptosis. Overall, our data provided a rationale to overcome the TMZ resistant in GBM treatment by inhibiting the cyclin E1 activity.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclina E/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Oncogênicas/antagonistas & inibidores , Temozolomida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina E/metabolismo , Feminino , Flavonoides/farmacologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Proteínas Oncogênicas/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Transplante Heterólogo
17.
Eur J Med Chem ; 176: 149-161, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103896

RESUMO

Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/análise , Alcaloides/síntese química , Alcaloides/isolamento & purificação , Animais , Benzodioxóis/análise , Benzodioxóis/síntese química , Benzodioxóis/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Piperidinas/análise , Piperidinas/síntese química , Piperidinas/isolamento & purificação , Alcamidas Poli-Insaturadas/análise , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/isolamento & purificação
18.
Scand J Immunol ; 90(3): e12791, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31132306

RESUMO

The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenases and have recently been found to have an anti-inflammatory activity. However, the role of EETs in non-alcoholic steatohepatitis has not been fully understood. In this study, we investigated the protective role of EETs in methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) in mice and the potential mechanisms. We used 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea(TPPU), a soluble epoxide hydrolase inhibitor, to increase the endogenous EET level in mice. Upon TPPU treatment, the liver steatosis and inflammatory damage were significantly ameliorated in mice with steatohepatitis, paralleled by the downregulation of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) as well as chemokines (CXCL1, MCP-1). Compared with untreated NASH mice, mRNA levels of sterol regulatory element binding protein 1c (SREBP1c) and inflammation relevant adhesion molecules (ICAM-1, VCAM-1) were downregulated, whereas mRNA level of peroxisome proliferator-activated receptor α(PPAR-α) was elevated in TPPU-treated mice. In vitro, 11,12-EET treatment remarkably attenuated free fatty acid (FFA)-induced inflammation in HepG2 and THP-1 cells. Further, 11,12-EET inhibited the activation of NF-κB signalling pathway in macrophages from mice with steatohepatitis. Collectively, these results suggest that EETs play a protective role and alleviate the MCD diet-induced steatohepatitis in mice mainly by downregulating activation of NF-κB pathway in macrophages.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dieta/efeitos adversos , Metionina/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Colina/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , PPAR alfa/metabolismo , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Células THP-1 , Molécula 1 de Adesão de Célula Vascular/metabolismo
19.
Expert Opin Investig Drugs ; 28(6): 555-567, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31081399

RESUMO

INTRODUCTION: Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development. AREAS COVERED: This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP-targeted drugs. EXPERT OPINION: Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Desenvolvimento de Medicamentos/métodos , Transtornos de Enxaqueca/tratamento farmacológico , Doença Aguda , Animais , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Humanos , Transtornos de Enxaqueca/fisiopatologia , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Triptaminas/efeitos adversos , Triptaminas/farmacologia
20.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
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