RESUMEN

The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease.

Asunto(s)

Corteza Prefrontal/metabolismo , Esquizofrenia/genética , Lóbulo Temporal/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Esquizofrenia/metabolismo

RESUMEN

A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.

Asunto(s)

Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Alquilación , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Diseño de Fármacos , Humanos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Serotonina/efectos de los fármacos , Proteínas Recombinantes/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacología

RESUMEN

Analysis of interactions between the C-terminal tail of the MOP-1 and MOP-1A variants of the human mu-opioid receptor with proteins derived from a human brain cDNA library resulted in identification of the actin and intermediate filament-binding protein periplakin. Mapping of this interaction indicated that the predicted fourth intracellular loop/helix VIII of the receptor interacts with the C-terminal rod and linker region of periplakin. Periplakin is widely expressed in the central nervous system of both man and rat and demonstrated an overlapping but not identical distribution with mu-opioid (MOP) receptors. Co-expression of periplakin with MOP-1 or a MOP-1-eYFP fusion construct in HEK293 cells did not interfere with agonist-mediated internalization of the receptor. When co-expressed with a MOP-1-Gi1 alpha fusion protein periplakin significantly reduced the capacity of the agonist to stimulate binding of 35S-labeled guanosine 5'-3-O-(thio)triphosphate ([35S]GTP gamma S) to the receptor-associated G protein. By contrast, periplakin did not interfere with agonist-stimulation of [35S]GTP gamma S binding to either an alpha 2A-adrenoreceptor-Gi1 alpha fusion protein or a beta2-adrenoreceptor-Gs alpha fusion protein, indicating its selectivity of function. This represents the first example of an opioid receptor-interacting protein that functions to disrupt agonist-mediated G protein activation.

Asunto(s)

Proteínas del Citoesqueleto/química , Proteínas de Unión al GTP/metabolismo , Receptores Opioides mu/química , Actinas/química , Secuencia de Aminoácidos , Biotina/farmacología , Encéfalo/metabolismo , Línea Celular , Membrana Celular/metabolismo , Sistema Nervioso Central/metabolismo , ADN/metabolismo , ADN Complementario/metabolismo , Biblioteca de Genes , Glutatión Transferasa/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Histidina/química , Humanos , Immunoblotting , Ligandos , Microscopía Confocal , Microscopía Fluorescente , Datos de Secuencia Molecular , Plaquinas , Unión Proteica , Isoformas de Proteínas , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Receptores Opioides mu/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Homología de Secuencia de Aminoácido , Distribución Tisular , Transfección , Técnicas del Sistema de Dos Híbridos

RESUMEN

The neurodegenerative disease first described almost 100 years ago by Alois Alzheimer is predicted to be one of the major health problems of the 21st century. Alzheimer's disease (AD) is a progressive dementia characterized by global cognitive decline and is defined pathologically by amyloid plaques and neurofibrillary tangles. Major unmet medical need has encouraged pharmaceutical companies to invest in AD drug development. Promising novel approaches are under way, assisted by recent advances in animal models and an increased understanding of pathophysiology. However, demonstration of disease modification and identification of at-risk individuals are among the significant challenges facing those working in AD drug development.