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1.
J Neuroinflammation ; 18(1): 213, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34537066

RESUMO

BACKGROUND: Inflammation in the central nervous system (CNS) is observed in many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling plays an essential role in modulating neuroinflammation. CYR119 is a CNS-penetrant sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling. We evaluated target engagement and the effects of CYR119 on markers of neuroinflammation in vitro in mouse microglial cells and in vivo in quinolinic acid (QA)-induced and high-fat diet-induced rodent neuroinflammation models. METHODS: Target engagement was verified in human embryonic kidney (HEK) cells, rat primary neurons, mouse SIM-A9 cells, and in rats by measuring changes in cGMP and downstream targets of sGC signaling [phosphorylated vasodilator-stimulated phosphoprotein (pVASP), phosphorylated cAMP-response element binding (pCREB)]. In SIM-A9 cells stimulated with lipopolysaccharides (LPS), markers of inflammation were measured when cells were treated with or without CYR119. In rats, microinjections of QA and vehicle were administered into the right and left hemispheres of striatum, respectively, and then rats were dosed daily with either CYR119 (10 mg/kg) or vehicle for 7 days. The activation of microglia [ionized calcium binding adaptor molecule 1 (Iba1)] and astrocytes [glial fibrillary acidic protein (GFAP)] was measured by immunohistochemistry. Diet-induced obese (DIO) mice were treated daily with CYR119 (10 mg/kg) for 6 weeks, after which inflammatory genetic markers were analyzed in the prefrontal cortex. RESULTS: In vitro, CYR119 synergized with exogenous NO to increase the production of cGMP in HEK cells and in primary rat neuronal cell cultures. In primary neurons, CYR119 stimulated sGC, resulting in accumulation of cGMP and phosphorylation of CREB, likely through the activation of protein kinase G (PKG). CYR119 attenuated LPS-induced elevation of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in mouse microglial cells. Following oral dosing in rats, CYR119 crossed the blood-brain barrier (BBB) and stimulated an increase in cGMP levels in the cerebral spinal fluid (CSF). In addition, levels of proinflammatory markers associated with QA administration or high-fat diet feeding were lower in rodents treated with CYR119 than in those treated with vehicle. CONCLUSIONS: These data suggest that sGC stimulation could provide neuroprotective effects by attenuating inflammatory responses in nonclinical models of neuroinflammation.


Assuntos
Anti-Inflamatórios/metabolismo , Sistema Nervoso Central/metabolismo , GMP Cíclico/metabolismo , Mediadores da Inflamação/metabolismo , Neurônios/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores/metabolismo , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Pharm Res ; 38(10): 1731-1745, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34671920

RESUMO

PURPOSE: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have shown promise in treating Duchenne muscular dystrophy (DMD). We evaluated a semi-mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) model to capture the relationship between plasma and muscle tissue exposure/response in mdx mice treated by mouse surrogate PPMO. METHODS: A single or repeated (every 4 weeks for 20 weeks) intravenous PPMO dose was administered to mdx mice (n = 6/timepoint). A PK/PD model was built to characterize data via sequential modeling. A 2-compartment model was used to describe plasma PK. A simultaneous tissue PK/PD model was subsequently developed: 2-compartment model to describe muscle PK; linked to an indirect response model describing stimulation of synthesis of skipped transcript, which was in turn linked to stimulation of synthesis of dystrophin protein expression. RESULTS: Model performance assessment via goodness-of-fit plots, visual predictive checks, and accurate parameter estimation indicated robust fits of plasma PK and muscle PK/PD data. The model estimated a PPMO tissue half-life of 5 days-a useful parameter in determining the longevity of PPMOs in tissue and their limited accumulation after multiple doses. Additionally, the model successfully described dystrophin expression after single dosing and associated protein accumulation after multiple dosing (increasing ~ twofold accumulation from the first to last dose). CONCLUSIONS: This first PK/PD model of a PPMO in a DMD disease model will help characterize and predict the time course of PK/PD biomarkers in mdx mice. Furthermore, the model framework can be used to develop clinical PK/PD models and can be extended to other exon-skipping therapies and species.


Assuntos
Peptídeos Penetradores de Células/química , Morfolinos/farmacocinética , Distrofia Muscular de Duchenne/tratamento farmacológico , Animais , Área Sob a Curva , Simulação por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Distrofina/genética , Distrofina/metabolismo , Meia-Vida , Humanos , Masculino , Camundongos Endogâmicos mdx , Modelos Biológicos , Modelos Estatísticos , Morfolinos/sangue
3.
Bioorg Med Chem Lett ; 22(8): 2943-7, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22424974

RESUMO

New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.


Assuntos
Amidas/síntese química , Descoberta de Drogas , Piperidinas/síntese química , Receptor de Colecistocinina A/agonistas , Amidas/química , Amidas/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Obesos , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacos
4.
Front Pharmacol ; 13: 852080, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308230

RESUMO

Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 weeks old, male C57BL/6N mice were either maintained on low-fat diet (LFD, lean mice) or placed on 60% high-fat diet (HFD, DIO mice). At 14 weeks old, the DIO mice were either maintained on HFD or switched to HFD with praliciguat (6-mg/kg). Day 28 samples were collected for biomarker analysis. In a second study under the same paradigm, indirect calorimetry was performed on days 8, 9, 20, 21, 32, and 33 and an oral lipid tolerance test (LTT) on day 38. Mice treated 28 days with praliciguat had lower levels of fasting plasma insulin, C-peptide, triglycerides, and HOMA-IR (homeostatic model assessment for insulin resistance) than DIO controls. In addition, energy expenditure was higher in praliciguat-treated than in DIO control mice on days 9, 20, 32, and 33; and day-38 triglycerides were lower. HFD-induced increases in gene expression of liver TNF-ɑ, lipoprotein lipase (Lpl), and patatin-like phospholipase domain-containing protein 3 (Pnpla3) in control DIO mice were attenuated in praliciguat-treated DIO mice. The positive metabolic effects observed in praliciguat-treated mice were associated with the restoration of liver PI3K (pAKT-Thr308) signaling, but not MAPK (pERK). In conclusion, praliciguat-treated DIO mice had increased energy utilization, improved insulin sensitivity, and lower plasma triglycerides. These results illustrate metabolic effects associated with praliciguat treatment in DIO mice.

5.
Cytokine ; 53(3): 311-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21177120

RESUMO

CC Chemokine ligand 22 (Ccl22) is a selective, high affinity ligand at the CC chemokine receptor 4 (Ccr4). We have identified cDNAs encoding both ligand and receptor of the Ccl22-Ccr4 pair in cDNA libraries of the anterior hypothalamus/pre-optic area (AH/POA) by PCR. The AH/POA is the key brain region where endogenous pyrogens have been shown to act on warm sensitive neurons to affect thermogenesis in brown adipose tissue (BAT) and other thermogenically responsive tissues. We show that functional Ccr4 receptors are present in the AH/POA neurons as injection of Ccl22 into the POA but not to other hypothalamic nuclei induces an increase in core body temperature as measured by radiotelemetry. Indomethacin (5 mg/kg s.c) pre-treatment markedly reduced the hyperthermia evoked by POA injection of Ccl22 (10 ng/0.5 ul) and thus suggests that this hyperthermia is mediated through cyclooxygenase activation and thus likely through the formation and action of the pyrogen prostaglandin E2. The temperature elevation involves a decrease in the respiratory exchange ratio and increased activation of the brown adipose tissue as demonstrated by ¹8F-FDG-PET imaging. We describe a novel role to the ligand Ccl22 and its receptor Ccr4 in the anterior hypothalamus in temperature regulation that depends on the synthesis of the endogenous pyrogen, prostaglandin E2.


Assuntos
Tecido Adiposo Marrom/metabolismo , Quimiocina CCL22/genética , Febre/fisiopatologia , Hipotálamo Anterior/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Temperatura Corporal/efeitos dos fármacos , Quimiocina CCL22/metabolismo , Quimiocina CCL22/farmacologia , Dinoprostona/metabolismo , Feminino , Febre/induzido quimicamente , Febre/prevenção & controle , Expressão Gênica , Hipotálamo Anterior/efeitos dos fármacos , Indometacina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Pirogênios/metabolismo , Pirogênios/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores CCR4/genética , Receptores CCR4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Telemetria , Tomografia Computadorizada por Raios X
6.
Front Pharmacol ; 12: 656561, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108877

RESUMO

Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these diseases increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Impairment of this pathway has been demonstrated in neurodegenerative diseases. Normalizing deficient NO-cGMP signaling could address multiple pathophysiological features of neurodegenerative diseases. sGC stimulators are small molecules that synergize with NO, activate sGC, and increase cGMP production. Many systemic sGC stimulators have been characterized and advanced into clinical development for a variety of non-central nervous system (CNS) pathologies. Here, we disclose the discovery of CY6463, the first brain-penetrant sGC stimulator in clinical development for the treatment of neurodegenerative diseases, and demonstrate its ability to improve neuronal activity, mediate neuroprotection, and increase cognitive performance in preclinical models. In several cellular assays, CY6463 was demonstrated to be a potent stimulator of sGC. In agreement with the known effects of sGC stimulation in the vasculature, CY6463 elicits decreases in blood pressure in both rats and mice. Relative to a non-CNS penetrant sGC stimulator, rodents treated with CY6463 had higher cGMP levels in cerebrospinal fluid (CSF), functional-magnetic-resonance-imaging-blood-oxygen-level-dependent (fMRI-BOLD) signals, and cortical electroencephalographic (EEG) gamma-band oscillatory power. Additionally, CY6463 improved cognitive performance in a model of cognitive disruption induced by the administration of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. In models of neurodegeneration, CY6463 treatment increased long-term potentiation (LTP) in hippocampal slices from a Huntington's disease mouse model and decreased the loss of dendritic spines in aged and Alzheimer's disease mouse models. In a model of diet-induced obesity, CY6463 reduced markers of inflammation in the plasma. Furthermore, CY6463 elicited an additive increase in cortical gamma-band oscillatory power when co-administered with donepezil: the standard of care in Alzheimer's disease. Together, these data support the clinical development of CY6463 as a novel treatment for neurodegenerative disorders.

7.
Biochem Biophys Res Commun ; 394(2): 366-71, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20211605

RESUMO

Cannabinoid CB(1) receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB(1) receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB(1) receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB(1) receptors in both binding (K(i)=0.7 nM) and functional assays (K(i)=0.2 nM). The compound has low affinity (K(i)=7600 nM) for human CB(2) receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB(1) receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB(1) receptor competitive antagonist that may further our understanding of the endocannabinoid system.


Assuntos
Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Piperidinas/farmacologia , Purinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Fármacos Antiobesidade/uso terapêutico , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Consumo de Oxigênio , Piperidinas/uso terapêutico , Purinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
8.
J Pharmacol Exp Ther ; 335(1): 103-13, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20605903

RESUMO

Cannabinoid-1 (CB(1)) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB(1) receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB(1)-selective antagonist 1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(methylamino) azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n = 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4-8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pair-fed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB(1) receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake.


Assuntos
Adiposidade/efeitos dos fármacos , Fármacos Antiobesidade , Azetidinas/farmacologia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Triazinas/farmacologia , Adiponectina/metabolismo , Animais , Azetidinas/farmacocinética , Glicemia/metabolismo , Dieta , Cães , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Determinação de Ponto Final , Comportamento Alimentar/efeitos dos fármacos , Teste de Tolerância a Glucose , Leptina/metabolismo , Lipídeos/sangue , Macaca fascicularis , Masculino , Ratos , Ratos Sprague-Dawley , Triazinas/farmacocinética , Redução de Peso/efeitos dos fármacos
9.
BMC Pharmacol ; 10: 9, 2010 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-20712891

RESUMO

BACKGROUND: Cannabinoid 1 (CB1) receptor antagonists exhibit pharmacological properties favorable for the treatment of obesity and other related metabolic disorders. CE-178253 (1-[7-(2-Chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid hydrochloride) is a recently discovered selective centrally-acting CB1 receptor antagonist. Despite a large body of knowledge on cannabinoid receptor antagonists little data exist on the quantitative pharmacology of this therapeutic class of drugs. The purpose of the current studies was to evaluate the quantitative pharmacology and concentration/effect relationships of CE-178253 based on unbound plasma concentration and in vitro pharmacology data in different in vivo preclinical models of FI and energy expenditure. RESULTS: In vitro, CE-178253 exhibits sub-nanomolar potency at human CB1 receptors in both binding (Ki = 0.33 nM) and functional assays (Ki = 0.07 nM). CE-178253 has low affinity (Ki > 10,000 nM) for human CB2 receptors. In vivo, CE-178253 exhibits concentration-dependent anorectic activity in both fast-induced re-feeding and spontaneous nocturnal feeding FI models. As measured by indirect calorimetry, CE-178253 acutely stimulates energy expenditure by greater than 30% in rats and shifts substrate oxidation from carbohydrate to fat as indicated by a decrease the respiratory quotient from 0.85 to 0.75. Determination of the concentration-effect relationships and ex vivo receptor occupancy in efficacy models of energy intake and expenditure suggest that a greater than a 2-fold coverage of the Ki (50-75% receptor occupancy) is required for maximum efficacy. Finally, in two preclinical models of obesity, CE-178253 dose-dependently promotes weight loss in diet-induced obese rats and mice. CONCLUSIONS: We have combined quantitative pharmacology and ex vivo CB1 receptor occupancy data to assess concentration/effect relationships in food intake, energy expenditure and weight loss studies. Quantitative pharmacology studies provide a strong a foundation for establishing and improving confidence in mechanism as well as aiding in the progression of compounds from preclinical pharmacology to clinical development.


Assuntos
Depressores do Apetite/farmacologia , Depressores do Apetite/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Triazinas/farmacologia , Triazinas/uso terapêutico , Redução de Peso/efeitos dos fármacos , Animais , Depressores do Apetite/metabolismo , Depressores do Apetite/farmacocinética , Azetidinas/metabolismo , Azetidinas/farmacocinética , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Triazinas/metabolismo , Triazinas/farmacocinética
10.
Bioorg Med Chem Lett ; 19(18): 5351-4, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19683918

RESUMO

A new series of CB(1) receptor antagonists incorporating an imidazole-based isosteric replacement for the hydrazide moiety of rimonabant (SR141716) is disclosed. Members of this imidazole series possess potent/selective binding to the rCB(1) receptor and exhibit potent hCB(1) functional activity. Isopropyl analog 9a demonstrated activity in the tetrad assay and was orally-active in a food intake model.


Assuntos
Imidazóis/química , Imidazóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Animais , Humanos , Imidazóis/farmacocinética , Modelos Moleculares , Conformação Molecular , Piperidinas/farmacocinética , Pirazóis/farmacocinética , Ratos , Rimonabanto , Relação Estrutura-Atividade
11.
Cell Rep ; 22(6): 1522-1530, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29425507

RESUMO

The age-related effects of GDF11 have been a subject of controversy. Here, we find that elevated GDF11 causes signs of cachexia in mice: reduced food intake, body weight, and muscle mass. GDF11 also elicited a significant elevation in plasma Activin A, previously shown to contribute to the loss of skeletal muscle. The effects of GDF11 on skeletal muscle could be reversed by administration of antibodies to the Activin type II receptors. In addition to the effects on muscle, GDF11 increased plasma GDF15, an anorectic agent. The anorexia, but not the muscle loss, could be reversed with a GDF15-neutralizing antibody. GDF15 upregulation is due to GDF11-induced recruitment of SMAD2/3 to the GDF15 promoter. Inhibition of GDF15 can restore appetite but cannot restore the GDF11-induced loss of muscle mass, which requires blockade of ActRII signaling. These findings are relevant for treatment of cachexia.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Caquexia , Fator 15 de Diferenciação de Crescimento/biossíntese , Fatores de Diferenciação de Crescimento/metabolismo , Ativinas/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/farmacologia , Fatores de Diferenciação de Crescimento/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima
12.
PLoS One ; 11(5): e0155674, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27227543

RESUMO

The purpose of this work is to develop a mathematical model of energy balance and body weight regulation that can predict species-specific response to common pre-clinical interventions. To this end, we evaluate the ability of a previously published mathematical model of mouse metabolism to describe changes in body weight and body composition in rats in response to two short-term interventions. First, we adapt the model to describe body weight and composition changes in Sprague-Dawley rats by fitting to data previously collected from a 26-day caloric restriction study. The calibrated model is subsequently used to describe changes in rat body weight and composition in a 23-day cannabinoid receptor 1 antagonist (CB1Ra) study. While the model describes body weight data well, it fails to replicate body composition changes with CB1Ra treatment. Evaluation of a key model assumption about deposition of fat and fat-free masses shows a limitation of the model in short-term studies due to the constraint placed on the relative change in body composition components. We demonstrate that the model can be modified to overcome this limitation, and propose additional measurements to further test the proposed model predictions. These findings illustrate how mathematical models can be used to support drug discovery and development by identifying key knowledge gaps and aiding in the design of additional experiments to further our understanding of disease-relevant and species-specific physiology.


Assuntos
Peso Corporal/efeitos dos fármacos , Restrição Calórica , Antagonistas de Receptores de Canabinoides/farmacologia , Metabolismo Energético/efeitos dos fármacos , Modelos Teóricos , Animais , Composição Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Ingestão de Energia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores
15.
ACS Med Chem Lett ; 4(1): 63-8, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900564

RESUMO

Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5.

16.
Metabolism ; 61(10): 1486-93, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22560055

RESUMO

The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. Dissipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis. Thus, we also measured the level of important regulators of metabolism. Downregulation of GPR83 was obtained by lentiviral short-hairpin RNAs (shGPR83) vectors designed and selected for their ability to reduce GPR83 levels in vitro. Mice received POA injection of shGPR83 or non-silencing vectors and were monitored for CBT, motor activity, food intake body weight and circulating levels of IGF-1, insulin, leptin and adiponectin. Down-regulation of GPR83 in the POA resulted in a small (0.15°C) but significant reduction of CBT during the dark/active cycle of the day. Temperature reduction was followed by increased body weight gain independent of caloric intake. shGPR83 mice also had increased level of circulating adiponectin (31916±952 pg/mL vs. 23474±1507 pg/mL, P<.01) while no change was observed for insulin, IGF-1 or leptin. GPR83 may participate in central thermoregulation and the central control of circulating adiponectin. Further work is required to determine how GPR83 can affect POA WSN and what are the long term metabolic consequences of its down-regulation.


Assuntos
Adiponectina/sangue , Regulação da Temperatura Corporal , Área Pré-Óptica/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Regulação para Baixo , Fator de Crescimento Insulin-Like I/análise , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Aumento de Peso
17.
ACS Med Chem Lett ; 3(5): 397-401, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900484

RESUMO

Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure-activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.

18.
Brain Res ; 1423: 1-9, 2011 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-22000082

RESUMO

Adiponectin can act in the brain to increase energy expenditure and reduce body weight by mechanisms not entirely understood. We found that adiponectin type 1 and type 2 receptors (AdipoR1 and AdipoR2) are expressed in warm sensitive neurons of the hypothalamic preoptic area (POA) which play a critical role in the regulation of core body temperature (CBT) and energy balance. Thus, we tested the ability of adiponectin to influence CBT in wild-type mice and in mice deficient for AdipoR1 or AdipoR2. Local injection of adiponectin into the POA induced prolonged elevation of core body temperature and decreased respiratory exchange ratio (RER) indicating that increased energy expenditure is associated with increased oxidation of fat over carbohydrates. In AdipoR1 deficient mice, the ability of adiponectin to raise CBT was significantly blunted and its ability to decrease RER was completely lost. In AdipoR2 deficient mice, adiponectin had only diminished hyperthermic effects but reduced RER similarly to wild type mice. These results indicate that adiponectin can contribute to energy homeostasis by regulating CBT by direct actions on AdipoR1 and R2 in the POA.


Assuntos
Adiponectina/farmacologia , Temperatura Corporal/efeitos dos fármacos , Área Pré-Óptica/citologia , Receptores de Adiponectina/metabolismo , Células Receptoras Sensoriais/fisiologia , Análise de Variância , Animais , Calorimetria Indireta , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Adiponectina/deficiência , Células Receptoras Sensoriais/efeitos dos fármacos , Telemetria , Sensação Térmica/efeitos dos fármacos , Sensação Térmica/fisiologia
19.
PLoS One ; 5(6): e11307, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20593012

RESUMO

BACKGROUND: Interventions for T2DM have in part aimed to mimic exercise. Here, we have compared the independent and combined effects of a PPARdelta agonist and endurance training mimetic (GW501516) and a myostatin antibody and resistance training mimetic (PF-879) on metabolic and performance outcomes in obese insulin resistant mice. METHODOLOGY/PRINCIPAL FINDINGS: Male ob/ob mice were treated for 6 weeks with vehicle, GW501516, PF-879, or GW501516 in combination with PF-879. The effects of the interventions on body composition, glucose homeostasis, glucose tolerance, energy expenditure, exercise capacity and metabolic gene expression were compared at the end of study. GW501516 attenuated body weight and fat mass accumulation and increased the expression of genes of oxidative metabolism. In contrast, PF-879 increased body weight by driving muscle growth and altered the expression of genes involved in insulin signaling and glucose metabolism. Despite their differences, both interventions alone improved glucose homeostasis. Moreover, GW501516 more effectively improved serum lipids, and PF-879 uniquely increased energy expenditure, exercise capacity and adiponectin levels. When combined the robust effects of GW501516 and/or PF-879 on body weight, adiposity, muscle mass, glycemia, serum lipids, energy expenditure and exercise capacity were highly conserved. CONCLUSIONS/SIGNIFICANCE: The data, for the first time, demonstrate postnatal inhibition of myostatin not only promotes gains in muscle mass similar to resistance training,but improves metabolic homeostasis. In several instances, these effects were either distinct from or complimentary to those of GW501516. The data further suggest that strategies to increase muscle mass, and not necessarily oxidative capacity, may effectively counter insulin resistance and T2DM.


Assuntos
Metabolismo Energético , Resistência à Insulina , Miostatina/antagonistas & inibidores , Obesidade/metabolismo , PPAR delta/agonistas , Adiponectina/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Composição Corporal , Citrato (si)-Sintase/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miostatina/imunologia , Condicionamento Físico Animal , Reação em Cadeia da Polimerase , Triglicerídeos/metabolismo
20.
Diabetes ; 59(1): 43-50, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19846801

RESUMO

OBJECTIVE: Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT). RESEARCH DESIGN AND METHODS: The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[(18)F]fluoro-2-deoxyglucose uptake into brown adipose tissue (BAT) was measured in rats after insulin treatment by positron emission tomography combined with X-ray computed tomography imaging. Insulin receptor-positive neurons were identified by retrograde tracing from the raphe pallidus. Insulin was locally applied on hypothalamic slices to determine the direct effects of insulin on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. RESULTS: Injection of insulin into the preoptic area of the hypothalamus induced a specific and dose-dependent elevation of CBT mediated by stimulation of BAT thermogenesis as shown by imaging and respiratory ratio measurements. Retrograde tracing indicates that insulin receptor-expressing warm-sensitive neurons activate BAT through projection via the raphe pallidus. Insulin applied on hypothalamic slices acted directly on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. The hyperthermic effects of insulin were blocked by pretreatment with antibodies to insulin or with a phosphatidylinositol 3-kinase inhibitor. CONCLUSIONS: Our findings demonstrate that insulin can directly modulate hypothalamic neurons that regulate thermogenesis and CBT and indicate that insulin plays an important role in coupling metabolism and thermoregulation at the level of anterior hypothalamus.


Assuntos
Temperatura Corporal/fisiologia , Hipertermia Induzida/métodos , Insulina/farmacologia , Neurônios/fisiologia , Tecido Adiposo Marrom/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Injeções , Insulina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/fisiologia , Telemetria
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