Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease.

We report the preparation and screening of a set of 55 pyridine dicarbonitriles as potential prion disease therapeutics. Use of microwave irradiation in an attempt to improve the synthesis typically led to only small enhancement in yields but gave cleaner reactions facilitating product isolation. The library was analysed for binding to human prion protein (huPrPC) by surface plasmon resonance and for inhibition of the formation of its partially protease resistant isoform PrPSc in mouse brain cells (SMB). A total of 26 compounds were found to bind to huPrPC whilst 12 showed discernable inhibition of PrPSc formation, five displaying EC(50)s in the range 2.5-9microwo compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50nM.

Virtual Reality for Anxiety Reduction Demonstrated by Quantitative EEG: A Pilot Study.

While previous research has established that virtual reality (VR) can be successfully used in the treatment of anxiety disorders, including phobias and PTSD, no research has examined changes in brain patterns associated with the use of VR for generalized anxiety management. In the current study, we compared a brief nature-based mindfulness VR experience to a resting control condition on anxious participants. Self-reported anxiety symptoms and resting-state EEG were recorded across intervals containing quiet rest or the VR intervention. EEG activity was analyzed as a function of global power shifts in Alpha and Beta activity, and with sLORETA current source density estimates of cingulate cortex regions of interest. Results demonstrated that both a quiet rest control condition and the VR meditation significantly reduced subjective reports of anxiety and increased Alpha power. However, the VR intervention uniquely resulted in shifting proportional power from higher Beta frequencies into lower Beta frequencies, and significantly reduced broadband Beta activity in the anterior cingulate cortex. These effects are consistent with a physiological reduction of anxiety. This pilot study provides preliminary evidence supporting the therapeutic potential of VR for anxiety management and stress reduction programs.

Library synthesis and screening: 2,4-diphenylthiazoles and 2,4-diphenyloxazoles as potential novel prion disease therapeutics.

Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective therapeutics are currently available. In this paper, we report on the synthesis and screening of a small library of 2,4-diphenylthiazol-5-ylamine and 2,4-diphenyloxazol-5-ylamine derivatives as potential novel prion disease therapeutics. Various synthetic strategies were investigated, including a novel phosgene-mediated cyclization of 2-N-benzoylphenylglycinonitrile, and a total of 45 compounds were synthesized. Library members were tested for both binding to prion protein (PrPC) using the surface plasmon resonance technique and for inhibition of PrPSc formation in persistently infected SMB cells. Of the compounds prepared, 15 were found to bind to human PrPC and six showed inhibition of PrPSc formation, displaying EC50s between 1.5 and 20 microM.