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2.
Mol Cell ; 54(1): 119-132, 2014 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-24657168

RESUMEN

The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.


Asunto(s)
Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas Portadoras/metabolismo , Quinasa de la Caseína II/metabolismo , Proteína Quinasa Activada por ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Fosfatos de Inositol/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas de Unión a Telómeros/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Linfocitos B/enzimología , Linfocitos B/patología , Sitios de Unión , Proteínas Portadoras/genética , Quinasa de la Caseína II/genética , Proteína Quinasa Activada por ADN/genética , Proteínas de Unión al ADN/genética , Estabilidad de Enzimas , Células HCT116 , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones Noqueados , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Proteínas Nucleares/genética , Fosforilación , Fosfotransferasas (Aceptor del Grupo Fosfato)/deficiencia , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Proteínas Proto-Oncogénicas c-ets/genética , Interferencia de ARN , Serina , Transducción de Señal , Proteínas de Unión a Telómeros/genética , Transfección , Proteína p53 Supresora de Tumor/genética
3.
Bioorg Med Chem Lett ; 29(19): 126628, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31445853

RESUMEN

Inositol hexakisphosphate kinases (IP6Ks) have been increasingly studied as therapeutically interesting enzymes. IP6K isoform specific knock-outs have been used to successfully explore inositol pyrophosphate physiology and related pathologies. A pan-IP6K inhibitor, N2-(m-trifluorobenzyl)-N6-(p-nitrobenzyl) purine (TNP), has been used to confirm phenotypes observed in genetic knock-out experiments; however, it suffers by having modest potency and poor solubility making it difficult to handle for in vitro applications in the absence of DMSO. Moreover, TNP's pan-IP6K inhibitory profile does not inform which IP6K isoform is responsible for which phenotypes. In this report we describe a series of purine-based isoform specific IP6K1 inhibitors. The lead compound was identified after multiple rounds of SAR and has been found to selectively inhibit IP6K1 over IP6K2 or IP6K3 using biochemical and biophysical approaches. It also boasts increased solubility and IP6K1 potency over TNP. These new compounds are useful tools for additional assay development and exploration of IP6K1 specific biology.


Asunto(s)
Fosfotransferasas (Aceptor del Grupo Fosfato)/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Isoformas de Proteínas , Relación Estructura-Actividad
4.
Proc Natl Acad Sci U S A ; 113(13): 3503-8, 2016 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-26976604

RESUMEN

The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL-CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC50 of 20 nM, acts as an intermolecular "glue," increasing cullin-CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL-CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL-CSN system and are potential targets for cancer therapy in conjunction with MLN4924.


Asunto(s)
Proteínas Cullin/metabolismo , Complejos Multiproteicos/metabolismo , Péptido Hidrolasas/metabolismo , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo , Ácido Fítico/biosíntesis , Secuencia de Aminoácidos , Complejo del Señalosoma COP9 , Dominio Catalítico , Proteínas Cullin/química , Proteínas Cullin/genética , Estabilidad de Enzimas , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Complejos Multiproteicos/química , Complejos Multiproteicos/genética , Péptido Hidrolasas/química , Péptido Hidrolasas/genética , Fosfotransferasas (Aceptor del Grupo Fosfato)/antagonistas & inhibidores , Fosfotransferasas (Aceptor del Grupo Fosfato)/química , Dominios y Motivos de Interacción de Proteínas , Homología de Secuencia de Aminoácido , Electricidad Estática , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
5.
Bioorg Med Chem Lett ; 28(19): 3231-3235, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30170942

RESUMEN

Due to increased interest in As(III) S-adenosylmethionine methyltransferase (AS3MT), a search for chemical probes that can help elucidate function was initiated. A homology model was built based on related enzymes, and virtual screening produced 426 potential hits. Evaluation of these compounds in a functional enzymatic assay revealed several modest inhibitors including an O-substituted 2-amino-3-cyano indole scaffold. Two iterations of near neighbor searches revealed compound 5 as a potent inhibitor of AS3MT with good selectivity over representative methyltransferases DOT1L and NSD2 as well as a representative set of diverse receptors. Compound 5 should prove to be a useful tool to investigate the role of AS3MT and a potential starting point for further optimization.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Metiltransferasas/antagonistas & inhibidores , Humanos
6.
Proc Natl Acad Sci U S A ; 112(6): 1773-8, 2015 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-25617365

RESUMEN

The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.


Asunto(s)
Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Fosfatos de Inositol/metabolismo , Metástasis de la Neoplasia/fisiopatología , Fosfotransferasas (Aceptor del Grupo Fosfato)/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP , Animales , Western Blotting , Adhesión Celular/fisiología , Línea Celular Tumoral , Matriz Extracelular/metabolismo , Humanos , Inmunoprecipitación , Fosfatos de Inositol/biosíntesis , Ratones , Ratones Desnudos , Microscopía Fluorescente , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo
7.
Mol Psychiatry ; 21(11): 1517-1526, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-26857598

RESUMEN

Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related potassium channel, is associated with impaired cognition, inefficient neural processing and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation. Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.


Asunto(s)
Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/fisiología , Cognición/fisiología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Hipocampo/fisiopatología , Humanos , Potenciación a Largo Plazo/fisiología , Memoria a Corto Plazo , Ratones , Ratones Transgénicos , Modelos Moleculares , Neuronas/metabolismo , Patología Molecular/métodos , Corteza Prefrontal/fisiopatología , Esquizofrenia/genética , Esquizofrenia/metabolismo
8.
Bioorg Med Chem Lett ; 26(12): 2952-2956, 2016 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-27133481

RESUMEN

A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.


Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Compuestos Heterocíclicos/farmacología , Piridonas/farmacología , Animales , Inhibidores de Catecol O-Metiltransferasa/síntesis química , Inhibidores de Catecol O-Metiltransferasa/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Modelos Moleculares , Estructura Molecular , Piridonas/síntesis química , Piridonas/química , Ratas , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 25(21): 4812-4819, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26195137

RESUMEN

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Hidantoínas/química , Hidantoínas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Hidantoínas/síntesis química , Metilación , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
10.
bioRxiv ; 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39211199

RESUMEN

Ribosome biosynthesis is a cancer vulnerability executed by targeting RNA polymerase I (Pol I) transcription. We developed advanced, specific Pol I inhibitors to identify drivers of this sensitivity. By integrating multi-omics features and drug sensitivity data from a large cancer cell panel, we discovered that RPL22 frameshift mutation conferred Pol I inhibitor sensitivity in microsatellite instable cancers. Mechanistically, RPL22 directly interacts with 28S rRNA and mRNA splice junctions, functioning as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promoted the splicing of its paralog RPL22L1 and p53 negative regulator MDM4. Chemical and genetic inhibition of rRNA synthesis broadly remodeled mRNA splicing controlling hundreds of targets. Strikingly, RPL22-dependent alternative splicing was reversed by Pol I inhibition revealing a ribotoxic stress-initiated tumor suppressive pathway. We identify a mechanism that robustly connects rRNA synthesis activity to splicing and reveals their coordination by ribosomal protein RPL22.

11.
J Med Chem ; 67(16): 13639-13665, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39096294

RESUMEN

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.


Asunto(s)
Barrera Hematoencefálica , Fosfotransferasas (Aceptor del Grupo Fosfato) , Barrera Hematoencefálica/metabolismo , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo , Fosfotransferasas (Aceptor del Grupo Fosfato)/antagonistas & inhibidores , Animales , Humanos , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ratones , Masculino , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/síntesis química , Ratas
12.
Biomolecules ; 13(9)2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37759717

RESUMEN

Inositol is a unique biological small molecule that can be phosphorylated or even further pyrophosphorylated on each of its six hydroxyl groups. These numerous phosphorylation states of inositol along with the kinases and phosphatases that interconvert them comprise the inositol phosphate signaling pathway. Inositol hexakisphosphate kinases, or IP6Ks, convert the fully mono-phosphorylated inositol to the pyrophosphate 5-IP7 (also denoted IP7). There are three isoforms of IP6K: IP6K1, 2, and 3. Decades of work have established a central role for IP6Ks in cell signaling. Genetic and pharmacologic manipulation of IP6Ks in vivo and in vitro has shown their importance in metabolic disease, chronic kidney disease, insulin signaling, phosphate homeostasis, and numerous other cellular and physiologic processes. In addition to these peripheral processes, a growing body of literature has shown the role of IP6Ks in the central nervous system (CNS). IP6Ks have a key role in synaptic vesicle regulation, Akt/GSK3 signaling, neuronal migration, cell death, autophagy, nuclear translocation, and phosphate homeostasis. IP6Ks' regulation of these cellular processes has functional implications in vivo in behavior and CNS anatomy.

13.
Behav Processes ; 212: 104941, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37673291

RESUMEN

Attention is a cognitive domain often disrupted in neuropsychiatric disorders and continuous performance tests (CPTs) are common clinical assays of attention. In CPTs, participants produce a behavioral response to target stimuli and refrain from responding to non-target stimuli. Performance in CPTs is measured as the ability to discriminate between targets and non-targets. Rodent versions of CPTs (rCPTs) have been validated with both anatomical and pharmacological studies, providing a translational platform for understanding attention function. In humans, stimulus degradation, the inclusion of visual noise in the image to reduce resolution, in CPTs impairs performance. Reduced image contrast, changes in the relative luminescence of elements in the image, has been used in rCPTs to test similar constructs, but, to our knowledge, reduced image resolution has not been tested in an rCPT. In this study, we tested multiple levels of stimulus degradation in a touchscreen version of the rCPT in mice. We found that stimulus degradation significantly decreased performance in males and females. Specifically, we found decreased stimulus discrimination and increases in hit reaction time and reaction time variability. These findings are in line with the effects of stimulus degradation in human studies. These data extend the utility and translational value of the family of rCPTs by demonstrating that stimulus degradation in the form of reduced image resolution produces qualitatively similar behavioral responses in mice as those in previous human studies.

14.
Biomolecules ; 13(5)2023 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-37238737

RESUMEN

Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, and NAFLD. Moreover, high-throughput screening (HTS) assays and structure-activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO WT C57/BL6J mice. LI-2242 (20 mg/kg/BW daily, i.p.) reduced body weight in DIO mice by specifically reducing the accumulation of body fat. It also improved glycemic parameters and reduced hyperinsulinemia. LI-2242-treated mice displayed reduced the weight of various adipose tissue depots and an increased expression of metabolism- and mitochondrial-energy-oxidation-inducing genes in these tissues. LI-2242 also ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and lipogenesis. Furthermore, LI-2242 enhances the mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. In conclusion, the pharmacologic inhibition of the inositol pyrophosphate pathway by LI-2242 has therapeutic potential in obesity and NAFLD.


Asunto(s)
Hiperglucemia , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Difosfatos/metabolismo , Insulina/metabolismo , Obesidad/etiología , Obesidad/genética , Dieta , Resistencia a la Insulina/fisiología , Hiperglucemia/metabolismo , Lípidos , Inositol/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Metabolismo de los Lípidos
15.
ACS Med Chem Lett ; 14(12): 1760-1766, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38116421

RESUMEN

A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.

16.
ACS Med Chem Lett ; 13(4): 608-614, 2022 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-35450366

RESUMEN

RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.

17.
Bioorg Med Chem Lett ; 21(9): 2646-9, 2011 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-21257308

RESUMEN

The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 µM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics.


Asunto(s)
Descubrimiento de Drogas , Fenómenos Electrofisiológicos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Canales Iónicos Sensibles al Ácido , Animales , Estructura Molecular , Fragmentos de Péptidos , Ratas , Bibliotecas de Moléculas Pequeñas , Canales de Sodio
18.
Bioorg Med Chem Lett ; 21(6): 1692-6, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21316226

RESUMEN

A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.


Asunto(s)
Amidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Animales , Ratones , Ratas , Ratas Wistar
19.
Neurosci Lett ; 740: 135423, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33069811

RESUMEN

Social isolation is a growing public health concern across the lifespan. Specifically, isolation early in life, during critical periods of brain development, increases the risk of psychiatric disorders later in life. Previous studies of isolation models in mice have shown distinct neurological abnormalities in various regions of the brain, but the mechanism linking the experience of isolation to these phenotypes is unclear. In this study, we show that ΔFosB, a long-lived transcription factor associated with neuronal activity, chronic stress, and drug-induced neuroplasticity, is upregulated in the prelimbic/infralimbic (PL/IL) region of the cortex and hippocampus of adult C57BL/6J mice transiently isolated for two weeks post-weaning. Additionally, a related transcription factor, FosB, is also increased in the PL/IL in socially isolated females.In contrast, both ΔFosB and FosB are increased in male mice isolated for six weeks from weaning until tissue collection. These results show that short-term isolation during the critical post-weaning period has long-lasting and sex-dependent effects on gene expression in brain and that FosB/ΔFosB expression provides a potential mechanistic link between post-weaning social isolation and associated neurological abnormalities.


Asunto(s)
Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Sistema Límbico/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Aislamiento Social/psicología , Destete , Animales , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Caracteres Sexuales
20.
J Pharmacol Exp Ther ; 335(2): 409-17, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20682849

RESUMEN

T-type calcium channels have been implicated in many behaviorally important neurophysiological processes, and altered channel activity has been linked to the pathophysiology of neurological disorders such as insomnia, epilepsy, Parkinson's disease, depression, schizophrenia, and pain. We have previously identified a number of potent and selective T-type channel antagonists (Barrow et al., 2007; Shipe et al., 2008; Yang et al., 2008). Here we describe the properties of the antagonist TTA-A2 [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl}ethyl)acetamide], assessed in patch-clamp experiments. TTA-A2 blocks T-type channels (Ca(v)3.1, 3.2, 3.3) voltage dependently and with high potency (IC(50) ∼100 nM). Stimulation at 3 Hz revealed additional use dependence of inhibition. A hyperpolarized shift of the channel availability curve and delayed channel recovery from inactivation suggest that the compound preferentially interacts with and stabilizes inactivated channels. The compound showed a ∼300-fold selectivity for Ca(v)3 channels over high-voltage activated calcium channels. Inhibitory effects on native T-type currents were confirmed in brain slice recordings from the dorsal lateral geniculate nucleus and the subthalamic nucleus. Furthermore, we demonstrate that in vivo T-type channel inhibition by TTA-A2 suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Ca(v)3.1 and Ca(v)3.3, suggesting the selective effect of TTA-A2 on recurrent thalamocortical network activity. The discovery of the potent and selective T-type channel antagonist TTA-A2 has enabled us to study the in vivo effects of pharmacological T-channel inhibition on arousal in mice, and it will help to explore the validity of these channels as potential drug targets for sleep-related and other neurological diseases.


Asunto(s)
Nivel de Alerta/efectos de los fármacos , Bencenoacetamidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Piridinas/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Bencenoacetamidas/química , Bencenoacetamidas/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/genética , Línea Celular , Clonación Molecular , Relación Dosis-Respuesta a Droga , Cuerpos Geniculados/efectos de los fármacos , Cuerpos Geniculados/metabolismo , Humanos , Activación del Canal Iónico/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Piridinas/química , Piridinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Trastornos del Despertar del Sueño/tratamiento farmacológico , Trastornos del Despertar del Sueño/metabolismo
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