RESUMEN
GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.
Asunto(s)
Receptores Acoplados a Proteínas G/agonistas , Urea/análogos & derivados , Amidas/química , Amidas/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Conformación Molecular , Unión Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/metabolismo , Relación Estructura-Actividad , Urea/metabolismoRESUMEN
The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Transducción de Señal/efectos de los fármacos , Inhibidores Enzimáticos/química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Modelos Moleculares , Estructura MolecularRESUMEN
The 2nd to 4th finger digit ratio (2D:4D) is a sexually dimorphic feature determined during gestation indexing prenatal androgen/estrogen levels. More 'feminized' 2D:4D phenotype has been demonstrated in schizophrenia versus same-sex controls. This study examined 2D:4D in adolescents with schizotypal personality disorder (SPD). Among normal controls, right 2D:4D was significantly greater (more feminized) in females than males. We replicated laterality effects; significant sex differences only on right. There were no significant sex differences among SPDs. Diagnostic group differences were restricted to White/Caucasian males with greater right 2D:4D in SPDs. Findings suggest disruptions in prenatal gonadal hormones in vulnerability for schizophrenia.