Phenotypic approaches for CNS drugs.

Central nervous system (CNS) drug development is plagued by high clinical failure rate. Phenotypic assays promote clinical translation of drugs by reducing complex brain diseases to measurable, clinically valid phenotypes. We critique recent platforms integrating patient-derived brain cells, which most accurately recapitulate CNS disease phenotypes, with higher throughput models, including immortalized cells, to balance validity and scalability.

Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate.

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery.

Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid /-Hydrolase Domain 6 (ABHD6).

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/β-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [F]JZP-MA-11 as the first PET ligand for imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET.

Cannabinoid receptor CB and CB interacting proteins: Techniques, progress and perspectives.

Cannabinoid receptors 1 and 2 (CB and CB) are implicated in a range of physiological processes and have gained attention as promising therapeutic targets for a number of diseases. Protein-protein interactions play an integral role in modulating G protein-coupled receptor (GPCR) expression, subcellular distribution and signaling, and the identification and characterization of these will not only improve our understanding of GPCR function and biology, but may provide a novel avenue for therapeutic intervention. A variety of techniques are currently being used to investigate GPCR protein-protein interactions, including Förster/fluorescence and bioluminescence resonance energy transfer (FRET and BRET), proximity ligation assay (PLA), and bimolecular fluorescence complementation (BiFC).

Chromenopyrazole-based High Affinity, Selective Fluorescent Ligands for Cannabinoid Type 2 Receptor.

Cannabinoid type 2 receptor (CBR) is an attractive target for the treatment of pain and inflammatory disorders. Availability of a selective CBR fluorescent ligand to study CBR expression and localization in healthy and disease conditions would greatly contribute to improving our understanding of this receptor. Herein, we report a series of chromenopyrazole-based CBR fluorescent ligands.

Development of selective, fluorescent cannabinoid type 2 receptor ligands based on a 1,8-naphthyridin-2-(1)-one-3-carboxamide scaffold.

Cannabinoid type 2 (CB) receptor has been implicated in several diseases and conditions, however no CB receptor selective drugs have made it to market. The aim of this study was to develop fluorescent ligands as CB receptor tools, to enable an increased understanding of CB receptor expression and signalling and thereby accelerate drug discovery. Fluorescent ligands have been successfully developed for other receptors, however none with adequate subtype selectivity or imaging properties have been reported for CB receptor.

Cannabinoid Receptor 2 Signalling Bias Elicited by 2,4,6-Trisubstituted 1,3,5-Triazines.

Cannabinoid receptor 2 (CB) is predominantly distributed in immune tissues and cells and is a promising therapeutic target for modulating inflammation. In this study we designed and synthesised a series of 2,4,6-trisubstituted 1,3,5-triazines with piperazinylalkyl or 1,2-diethoxyethane (PEG2) chains as CB agonists, all of which were predicted to be considerably more polar than typical cannabinoid ligands. In this series, we found that triazines containing an adamantanyl group were conducive to CB binding whereas those with a cyclopentyl group were not.