Synthesis and evaluation of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives as FFA4 agonists.

Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives were designed and synthesized, featuring OC and SO2-N linkage. For the OC linkage compounds, 1g showed the most potent FFA4 agonistic activity with a pEC of 5.

Identification and target-pathway deconvolution of FFA4 agonists with anti-diabetic activity from Arnebia euchroma (Royle) Johnst.

FFA4 is a novel therapeutic target for the treatment of metabolic diseases, such as type II diabetes. However, there are still few ligands with structural diversity, selectivity and high potency, and the signaling pathway downstream of FFA4 remains to be poorly characterized. In this study, a high performance liquid chromatography-corona charged aerosol detector (HPLC-CAD) combined with label-free dynamic mass redistribution (DMR) method was introduced to guide the discovery of FFA4 agonists from Arnebia euchroma (Royle) Johnst.

Systematic characterization of AT1 receptor antagonists with label-free dynamic mass redistribution assays.

Introduction: In the drug discovery field, the binding affinities and binding kinetics of drug candidates are very important. Angiotensin II type 1 (AT1) receptor antagonists, e.g.

Phenotypic assessment and ligand screening of ETA/ETB receptors with label-free dynamic mass redistribution assay.

Endothelin receptors, consisting of two subtypes, ETA and ETB, are expressed in various tissues and widely regulate cardiovascular systems. The two receptors show distinct biological characteristics and are involved in different downstream pathways. Hence, to evaluate the ETA and ETB receptors on the same platform is helpful to display their pharmacological features.

Isolation and bioactive evaluation of flavonoid glycosides from Lobelia chinensis Lour using two-dimensional liquid chromatography combined with label-free cell phenotypic assays.

Flavonoid glycosides are widespread in herbs and often used as medicines and nutraceuticals because of good bioactivities and low toxicities. However, due to their structural complexity and diversity, isolation of flavonoid glycosides and evaluation of their bioactivities are still highly challenging. To solve this problem, a new method for separation and preparation of novel flavonoid glycosides from Lobelia chinensis Lour (L.

Label-free cell phenotypic study of FFA4 and FFA1 and discovery of novel agonists of FFA4 from natural products.

In this article, pharmacological studies of the free fatty acid receptor (FFA) 4 and FFA1 were conducted in transfected CHO cells (FFA4&FFA1) and HT29 cells with application of a label-free dynamic mass redistribution (DMR) assay. Commercially available compounds including α-linolenic acid (ALA), GW9508, TUG891, GSK137647A, TAK875, MEDICA16, AH7614 and GW1100, were used to validate the assay; real-time tracing of ligand-induced cell responses elucidated pharmacological properties of ligand-receptor interactions. A pool of 140 natural compounds was screened using the CHO-FFA4 cells.

Discovery of novel antagonists on β-adrenoceptor from natural products using a label-free cell phenotypic assay.

Label-free cell phenotypic assays were performed to establish a β-adrenoceptor (β-AR) target model in A431 cells and a β-AR target model in transfected HEK293-β cells, using known β-AR and β-AR agonists and antagonists. A list of natural compounds was screened on the target models, among which seven new compounds were found to be antagonistically active against β-AR. After receptor specificity evaluations on hydroxyl carboxylic acid receptor-2 (ΗΧΑ-2), histamine receptor (HR), and β-adrenoceptor (β-AR), six out of the seven compounds, including nuciferine, epiberberine, harmaline, harmine, palmatine, and columbamine, exhibited specific antagonistic activity against β-AR.

SAR Studies of -[2-(1-Tetrazol-5-yl)phenyl]benzamide Derivatives as Potent G Protein-Coupled Receptor-35 Agonists.

G protein-coupled receptor-35 (GPR35) has emerged as a potential target in the treatment of pain and inflammatory and metabolic diseases. We have discovered a series of potent GPR35 agonists based on a coumarin scaffold and found that the introduction of a 1tetrazol-5-yl group significantly increased their potency. We designed and synthesized a new series of [2-(1tetrazol-5-yl)phenyl]benzamide derivatives through a two-step synthetic approach, and characterized their agonistic activities against GPR35 using a dynamic mass redistribution (DMR) assay.

Discovery of 2H-Chromen-2-one Derivatives as G Protein-Coupled Receptor-35 Agonists.

A family of 2H-chromen-2-one derivatives were identified as G protein-coupled receptor-35 (GPR35) agonists using dynamic mass redistribution assays in HT-29 cells. The compounds with 1H-tetrazol-5-yl in 3-substituted position displayed higher potency than the corresponding carboxyl analogs, and the hydroxyl group in the 7-position also played an important role in GPR35 agonistic activity. 6-Bromo-7-hydroxy-8-nitro-3-(1H-tetrazol-5-yl)-2H-chromen-2-one (50) was found to be the most potent GPR35 agonist with an EC of 5.

Label-free cell phenotypic profiling and pathway deconvolution of neurotensin receptor-1.

Neurotensin (NT), an endogenous peptide found in the central nervous system and in peripheral tissues, contributes to the pathophysiology of neurodegenerative and psychiatric diseases, cancer, inflammation, and immunomodulatory disease. NT exerts its physiological effects predominantly through its cognate high-affinity neurotensin receptor-1 (NTS1). NTS1 emerges as a druggable target; however, there are limited numbers of NTS1 active compounds reported to date.

Anti-gastric cancer activity in three-dimensional tumor spheroids of bufadienolides.

Multicellular spheroids of cancer cells have been increasingly used to screen anti-tumor compounds, owing to their in vivo like microenvironment and structure as well as compatibility to high-throughput/high-content screening. Here we report the potency and efficacy of a family of bufadienolides to inhibit the growth of gastric cancer cell line HGC-27 in three-dimensional (3D) spheroidal models. Examining the morphological and growth patterns of several cell lines in round-bottomed ultra-low attachment microplate suggested that HGC-27 cells formed reproducibly multicellular spheroidal structures.