Photo-BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor.

The field of G protein-coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, i.e., photoswitchable ligands. Most of the developed tools have targeted the Rhodopsin-like family (Class A), the largest family of GPCRs. However, to date, all such Class A photoswitchable ligands were designed to act at the orthosteric binding site of these receptors. Herein, we report the development of the first photoswitchable allosteric modulators of Class A GPCRs, designed to target the M1 muscarinic acetylcholine receptor. The presented benzyl quinolone carboxylic acid (BQCA) derivatives, Photo-BQCisA and Photo-BQCtrAns, exhibit complementary photopharmacological behavior and allow reversible control of the receptor using light as an external stimulus. This makes them valuable tools to further investigate M1 receptor signaling and a proof of concept for photoswitchable allosteric modulators at Class A receptors.

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells.

New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.

Momentary affect predicts bodily movement in daily life: an ambulatory monitoring study.

There is converging evidence that physical activity influences affective states. It has been found that aerobic exercise programs can significantly diminish negative affect. Moreover, among healthy individuals, moderate levels of physical activity seem to increase energetic arousal and positive affect. However, the predictive utility of affective states for bodily movement has rarely been investigated. In this study, we examined whether momentarily assessed affect is associated with bodily movement in everyday life. Using a previously published data set (Schwerdtfeger, Eberhardt, & Chmitorz, 2008), we reanalyzed 12-hr ecological momentary assessment (EMA) data from 124 healthy volunteers. Electronic momentary positive-activated affect (EMA-PAA) and negative affect (EMA-NA) were assessed via handheld computers, and bodily movement was recorded via accelerosensors. Generalized linear mixed models were calculated. Results indicated that EMAPAA increases were accompanied by bodily movement increases of varying intensity. EMA-NA was also positively associated with increases in certain kinds of bodily movement. In light of previous research, this finding suggests that affect and bodily movement may have circular effects on each other.