RESUMEN
We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of alpha3- and alpha6-containing nicotinic receptors. In particular, compound 17a from this series is a potent alpha3beta4 and alpha6/4beta4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of alpha3beta4 and alpha6/4beta4 nicotinic receptors in CNS pharmacology.
Asunto(s)
Compuestos de Azabiciclo/química , Agonistas Nicotínicos/química , Receptores Nicotínicos/química , Sulfonamidas/química , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/farmacología , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of alpha7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity alpha7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Carbamatos/síntesis química , Agonistas Nicotínicos/síntesis química , Fenilcarbamatos/síntesis química , Receptores Nicotínicos/química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Carbamatos/química , Carbamatos/farmacocinética , Línea Celular , Humanos , Masculino , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacocinética , Fenilcarbamatos/química , Fenilcarbamatos/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.
Asunto(s)
Antipsicóticos/farmacología , Cuerpo Estriado/enzimología , Papaverina/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Catalepsia/inducido químicamente , Estimulantes del Sistema Nervioso Central/farmacología , Cuerpo Estriado/metabolismo , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/fisiología , Dextroanfetamina/farmacología , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitadores/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Haloperidol/farmacología , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Fenciclidina/farmacología , Fosforilación , RatasRESUMEN
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
Asunto(s)
Benzazepinas/síntesis química , Agonistas Nicotínicos/síntesis química , Quinoxalinas/síntesis química , Receptores Nicotínicos/efectos de los fármacos , Cese del Hábito de Fumar/métodos , Animales , Benzazepinas/química , Benzazepinas/farmacología , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Humanos , Técnicas In Vitro , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Quinoxalinas/química , Quinoxalinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Nicotínicos/fisiología , Vareniclina , Xenopus laevisRESUMEN
Compounds that interfere with the synthesis of either mitochondrial DNA or mtDNA-encoded proteins reduce the levels of 13 proteins essential for oxidative phosphorylation, leading to a decrease in mitochondrial adenosine triphosphate (ATP) production. Toxicity caused by these compounds is seldom identified in 24- to 72-h cytotoxicity assays due to the low turnover rates of both mtDNA and mtDNA-encoded proteins. To address this problem, the authors developed a 96-well format, high-content screening (HCS) assay that measures, in eukaryotic cells, the level of Complex IV-subunit 1, an mtDNA-encoded protein synthesized on mitochondrial ribosomes, and the level of Complex V-alpha subunit, a nuclear DNA-encoded protein synthesized on cytosolic ribosomes. The effect of several antibiotics and antiretrovirals on these 2 proteins was assessed, in transformed human liver epithelial cells, 6 days after compound treatment. The results confirmed effects of drugs known to reduce mtDNA-encoded protein levels and also revealed novel information showing that several fluoroquinolones and a macrolide, josamycin, impaired expression of mtDNA-encoded proteins. The HCS assay was robust with an average Z' factor of 0.62. The assay enables large-scale screening of compounds to identify those that potentially affect mtDNA-encoded protein levels and can be implemented within a screening paradigm to minimize compound attrition.
Asunto(s)
ADN Mitocondrial/genética , Células Eucariotas/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Proteínas Mitocondriales/metabolismo , Inhibidores de la Síntesis de la Proteína/aislamiento & purificación , Inhibidores de la Síntesis de la Proteína/farmacología , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antirretrovirales/aislamiento & purificación , Antirretrovirales/farmacología , Línea Celular Transformada , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/metabolismo , Eficiencia , Complejo IV de Transporte de Electrones/efectos de los fármacos , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Eucariotas/metabolismo , Fluoroquinolonas/aislamiento & purificación , Fluoroquinolonas/farmacología , Humanos , Josamicina/aislamiento & purificación , Josamicina/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Proteínas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/efectos de los fármacos , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/análisisRESUMEN
A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Nootrópicos/síntesis química , Nootrópicos/farmacología , Oxazoles/síntesis química , Oxazoles/farmacología , Receptores Nicotínicos/química , Esquizofrenia/tratamiento farmacológico , Animales , Compuestos de Azabiciclo/química , Disponibilidad Biológica , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Agonistas Nicotínicos/química , Nootrópicos/química , Oocitos/efectos de los fármacos , Oxazoles/química , Ratas , Piel/citología , Piel/efectos de los fármacos , Relación Estructura-Actividad , Xenopus laevis/crecimiento & desarrollo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist developed as a smoking cessation aid, showed antidepressant-like activity in the forced swim test in two mouse strains. In addition, a low varenicline dose significantly enhanced the effects of moderately active doses of the selective serotonin reuptake inhibitor sertraline. These findings are consistent with the notion that reducing alpha4beta2 nicotinic acetylcholine receptor activity either by antagonists or by partial agonists that can partially activate or desensitize acetylcholine receptors is associated with antidepressant-like properties. These data suggest that varenicline may have antidepressant potential and can, when combined, augment antidepressant responses of selective serotonin reuptake inhibitors.
Asunto(s)
Antidepresivos/farmacología , Benzazepinas/farmacología , Depresión/tratamiento farmacológico , Agonistas Nicotínicos/farmacología , Quinoxalinas/farmacología , Animales , Antidepresivos/administración & dosificación , Benzazepinas/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Agonistas Nicotínicos/administración & dosificación , Quinoxalinas/administración & dosificación , Receptores Nicotínicos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sertralina/farmacología , Natación , VareniclinaRESUMEN
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).