Hit-to-lead optimization of pyrrolo[1,2-a]quinoxalines as novel cannabinoid type 1 receptor antagonists.

Hit-to-lead optimization of a novel series of N-alkyl-N-[2-oxo-2-(4-aryl-4H-pyrrolo[1,2-a]quinoxaline-5-yl)-ethyl]-carboxylic acid amides, derived from a high throughput screening (HTS) hit, are described. Subsequent optimization led to identification of in vitro potent cannabinoid 1 receptor (CB1R) antagonists representing a new class of compounds in this area.

Comparative pharmacology of adrenergic alpha(2C) receptors coupled to Ca(2+) signaling through different Galpha proteins.

Adrenergic alpha(1), alpha(2) and beta receptors are members of the G-protein-coupled receptor families (GPCRs) mediating physiological responses to adrenaline (epinephrine) and noradrenaline (norepinephrine). Since GPCRs are major targets for potential therapeutic agents, development of robust, reliable and cost effective functional screening methods for these receptors is in the focus of pharmacological research. For this reason, the aim of the present study was to develop an intracellular calcium assay for investigating the pharmacology of the alpha(2C) type of adrenergic receptors (alpha(2C)-AR).

A high throughput luminescent assay for glycogen synthase kinase-3beta inhibitors.

A high throughput luminescent assay based on the Kinase-Glo() system (Promega, Madison, WI) has been developed for screening against glycogen synthase kinase-3beta (GSK-3beta). Careful optimization of assay parameters allowed us to develop a robust, reproducible, and sensitive assay. Its usefulness has been demonstrated in a high throughput screening run when screening 55,000 compounds.

Comparative virtual and experimental high-throughput screening for glycogen synthase kinase-3beta inhibitors.

Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. As an initial step of our lead discovery program, we developed a virtual screen to discriminate known GSK-3beta inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF = 28) suggests that our protocol identifies potential GSK-3beta inhibitors effectively from large compound collections.