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1.
J Med Chem ; 66(14): 9418-9444, 2023 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-37442941

RESUMEN

The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.


Asunto(s)
Hiperparatiroidismo Secundario , Insuficiencia Renal Crónica , Animales , Cinacalcet/farmacología , Cinacalcet/uso terapéutico , Naftalenos/farmacología , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Hormona Paratiroidea/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Calcio
2.
Biochem Biophys Res Commun ; 637: 267-275, 2022 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-36410276

RESUMEN

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Inhibidores de las Quinasa Fosfoinosítidos-3 , Humanos , Linfocitos B , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Línea Celular Tumoral
3.
Eur J Pharmacol ; 891: 173685, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33127363

RESUMEN

α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.


Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Colinérgicos/farmacología , Cognición/efectos de los fármacos , Disfunción Cognitiva/prevención & control , Trastornos Neurológicos de la Marcha/prevención & control , Filtrado Sensorial/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/efectos de los fármacos , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Línea Celular Tumoral , Colinérgicos/farmacocinética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Modelos Animales de Enfermedad , Perros , Conducta Exploratoria/efectos de los fármacos , Trastornos Neurológicos de la Marcha/metabolismo , Trastornos Neurológicos de la Marcha/fisiopatología , Trastornos Neurológicos de la Marcha/psicología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/fisiopatología , Masculino , Ratones Endogámicos BALB C , Prueba de Campo Abierto/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Transducción de Señal , Conducta Social , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo
4.
J Med Chem ; 63(3): 944-960, 2020 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-31755711

RESUMEN

The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.


Asunto(s)
Descubrimiento de Drogas , Agonistas Nicotínicos/farmacología , Nootrópicos/farmacología , Sulfonamidas/farmacología , Tiofenos/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Encéfalo/metabolismo , Ensayos Clínicos como Asunto , Estabilidad de Medicamentos , Humanos , Masculino , Estructura Molecular , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacocinética , Nootrópicos/síntesis química , Nootrópicos/farmacocinética , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Tiofenos/síntesis química , Tiofenos/farmacocinética
5.
Med Mol Morphol ; 52(1): 36-43, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29959534

RESUMEN

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, and hepatocyte injury with or without fibrosis. In this study, we explored the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor, on the progression of steatohepatitis in a murine model of NASH with diabetes. A novel NASH model with diabetes was generated by administration of streptozotocin injection to neonatal C57BL/6 mice (2-3 days old) combined with a high-fat diet feeding from the age of 4 weeks. The plasma biochemical parameters, oxidative stress, inflammation and histopathological changes were assessed. APD668 alone showed reduction in plasma glucose (- 39%, P < 0.05) and triglyceride level (- 26%) whereas a combined treatment of APD668 with linagliptin resulted in a more pronounced reduction in plasma glucose (- 52%, P < 0.001) and triglyceride (- 50%, P < 0.05) in NASH mice. In addition, co-administration of APD668 with linagliptin demonstrated a significant decrease in hepatic triglyceride, NAS score, hepatic TBARS and hepatic TNF-α in NASH mice with diabetes. These findings suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of NASH.


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Linagliptina/farmacología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Dieta Alta en Grasa , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Progresión de la Enfermedad , Fibrosis , Inflamación , Linagliptina/uso terapéutico , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas
6.
Expert Opin Ther Targets ; 22(7): 615-628, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29911915

RESUMEN

INTRODUCTION: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer's disease (AD), Parkinson's disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists. Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders. Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.


Asunto(s)
Polipéptido Inhibidor Gástrico/análogos & derivados , Enfermedades Neurodegenerativas/fisiopatología , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Desarrollo de Medicamentos/métodos , Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Incretinas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Receptores de la Hormona Gastrointestinal/metabolismo , Transducción de Señal/efectos de los fármacos
7.
Psychopharmacology (Berl) ; 235(5): 1557-1570, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29502275

RESUMEN

RATIONALE AND OBJECTIVES: 5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes. METHODS: In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3 mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14 days from the first day of ICV-STZ. RESULTS: Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5 mg/kg) and antagonist SB-399885 (10 mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible. CONCLUSION: The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.


Asunto(s)
Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Receptores de Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Estreptozocina/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Estreptozocina/administración & dosificación
8.
Eur J Pharmacol ; 828: 31-41, 2018 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-29577894

RESUMEN

Huntington's disease (HD) is an inherited complex progressive neurodegenerative disorder with an established etiopathology linked to neuronal oxidative stress and corticostriatal excitotoxicity. Present study explores the effects of glucose-dependent insulinotropic polypeptide (GIP) receptor agonist on the neurobehavioral sequelae of quinolinic acid-induced phenotype of Huntington's disease in rats. Bilateral administration of quinolinic acid (300 nmol/4 µl) to the rat striatum led to characteristic deficits in, locomotor activity, motor coordination, neuromuscular coordination and short-term episodic memory. Therapeutic treatment for 14 days with a stable and brain penetrating GIP receptor agonist, D-Ala2GIP (100 nmol/kg, i.p.), attenuated the neurobehavioral deficits due to quinolinic acid (QA) administration. Protective actions of D-Ala2GIP were sensitive to blockade with a GIP receptor antagonist, (Pro3)GIP (50 nmol/kg, i.p.), indicating specific involvement of GIP receptor signaling pathway. Stimulation of GIP receptor with D-Ala2GIP attenuated lipid peroxidation, evidenced by reduced levels of brain malondialdehyde (MDA), and restoration of reduced glutathione (GSH) levels in brain. Quinolinic acid administration led to significant loss of striatal monoamines, e.g., norepinephrine, epinephrine, serotonin, dopamine, and metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-Hydroxyindoleacetic acid (5-HIAA). D-Ala2GIP attenuated the QA-induced depletion of striatal monoamines, without affecting the monoamine degradation pathways. Thus, observed effects with D-Ala2GIP in the QA-induced Huntington's disease model could be attributable to reduction in lipid peroxidation, restoration of endogenous antioxidants and decreased striatal monoamine levels. These findings together suggest that stimulation of GIP receptor signaling pathway in brain could be a potential therapeutic strategy in the symptomatic management of Huntington's disease.


Asunto(s)
Conducta Animal/efectos de los fármacos , Monoaminas Biogénicas/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Enfermedad de Huntington/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Neostriado/metabolismo , Receptores de la Hormona Gastrointestinal/agonistas , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Marcha/efectos de los fármacos , Polipéptido Inhibidor Gástrico/química , Glutatión/metabolismo , Fuerza de la Mano , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/fisiopatología , Locomoción/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Memoria Episódica , Neostriado/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Ácido Quinolínico/efectos adversos , Ratas , Ratas Wistar
9.
Biochem Biophys Res Commun ; 495(2): 1608-1613, 2018 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-29203247

RESUMEN

Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs. On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (-78%) and cholesterol (-56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (-19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis.


Asunto(s)
Linagliptina/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Animales , Dieta Alta en Grasa/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Aumento de Peso/efectos de los fármacos
10.
Eur J Pharmacol ; 804: 38-45, 2017 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-28366809

RESUMEN

The aim of the present study was to evaluate the ability of D-Ala2GIP, a gastric inhibitory polypeptide (GIP) receptor agonist, to attenuate the behavioral phenotype of Parkinson's disease caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice. In the behavioral studies, MPTP administration led to spontaneous locomotor activity deficits, impaired rotarod performance, akinesia, muscular rigidity and increased tremor amplitude, which was attenuated by pretreatment with D-Ala2GIP (50-100 nmol/kg, i.p.). This acute neuroprotective response by D-Ala2GIP was found to be blocked by a selective GIP receptor antagonist, (Pro3)GIP (50 nmol/kg, i.p.), indicating that the observed effects are mediated through GIP receptor mediated signaling pathway. Biochemical studies revealed that D-Ala2GIP reduced the brain malondialdehyde levels and enhanced the brain glutathione levels, thereby mitigating the MPTP-induced oxidative stress. MPTP administration resulted in reduction of the striatal concentration of dopamine and its metabolites, homovanillic acid (HVA) and 3, 4-Dihydroxyphenylacetic acid (DOPAC). Pretreatment with D-Ala2GIP attenuated the loss of striatal dopamine levels without affecting the normal dopamine catabolism. Thus, the observed effects in the MPTP-induced Parkinsonism model could be in part attributable to the antioxidant properties of D-Ala2GIP and enhanced turnover of dopamine in the nigrostriatal pathways in mouse brain. These findings together suggest that GIP receptor could be a therapeutic target in the management of symptoms of Parkinson's disease.


Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Polipéptido Inhibidor Gástrico/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Dopamina/metabolismo , Polipéptido Inhibidor Gástrico/química , Polipéptido Inhibidor Gástrico/uso terapéutico , Glutatión/metabolismo , Ácido Homovanílico/metabolismo , Locomoción/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neostriado/patología , Neuronas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Temblor/tratamiento farmacológico
11.
Neurochem Res ; 42(5): 1571-1579, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28271324

RESUMEN

Beta-amyloid peptide (Aß) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer's disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against Aß-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The Aß25-35 (50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented Aß25-35-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aß25-35-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aß25-35 induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD.


Asunto(s)
Péptidos beta-Amiloides/toxicidad , Fragmentos de Péptidos/toxicidad , Receptores de Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Indoles/farmacología , Células PC12 , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Sulfonamidas/farmacología
12.
Eur J Pharmacol ; 801: 35-45, 2017 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-28274625

RESUMEN

G-protein coupled receptor 119 (GPR119) receptor is a rhodopsin-like, class A Gαs-coupled receptor, predominantly expressed in pancreatic islet cells and intestinal entero-endocrine cells. GPR119 has been emerged as a novel therapeutic target for the treatment of dyslipidemia in type 2 diabetes. In this study, we investigated the effect of APD668, a GPR119 agonist alone and in combination with linagliptin, a DPPIV inhibitor on oral fat tolerance test. Our findings demonstrate that APD668, a GPR119 agonist inhibits the intestinal triglyceride absorption after acute fat load in mice. Single dose administration of APD668 increases incretin secretion and enhances total PYY levels in presence of fat load in mice. We found that, the anti-dyslipidemic action of APD668 was reversed in presence of exendin-3 in oral fat tolerance test. In addition, our results showed that exendin-3 (9-39) failed to block the effect of APD668 on gastric emptying indicating that gastric emptying effects of APD668 are indeed mediated through GPR119 receptor dependent mechanism. Combined administration of APD668 and linagliptin significantly increased plasma active GLP-1 levels in-vivo and showed improvement in fat tolerance. However, APD668 failed to show anti-dyslipidemic activity in tyloxapol-induced hyperlipidemia in mice. Furthermore, we investigated the chronic effects of APD668 on hepatic steatosis in high trans-fat diet fed steatohepatitis model in mice. Oral administration of APD668 in HTF diet fed mice ameliorated hepatic endpoints such as plasma ALT, AST, liver weight and steatosis. These findings suggest that GPR119 agonists may represent a promising therapeutic strategy for the treatment of dyslipidemia and non-alcoholic steatohepatitis.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Interacciones Farmacológicas , Vaciamiento Gástrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Linagliptina/farmacología , Masculino , Mesilatos/farmacología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Oxadiazoles/farmacología , Polietilenglicoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Tetrazoles/farmacología , Tiazoles/farmacología , Triglicéridos/sangre
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