2 research outputs found
Eosinophils adhesion assay as a tool for phenotypic drug screening - The pharmacology of 1,3,5 – Triazine and 1H-indole like derivatives against the human histamine H4 receptor
Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H4 receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H4 receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H4 receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H4 receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H4 receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery
Novel Aryloxyethyl Derivatives of 1(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity
Novel
1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed
as “biased agonists” of serotonin 5-HT1A receptors.
The compounds were tested in signal transduction assays (ERK1/2 phosphorylation,
cAMP inhibition, Ca2+ mobilization, and β-arrestin
recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl
derivatives. The novel series showed high 5-HT1A receptor
affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, serotonin 5-HT2A, histamine
H1, and muscarinic M1 receptors, and favorable
druglike properties (CNS-MPO, Fsp3, LELP). The lead structure,
(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone
(17, NLX-204), displayed high selectivity in the SafetyScreen44
panel (including hERG channel), high solubility, metabolic stability,
and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes,
or P-glycoprotein. Preliminary in vivo studies confirmed its promising
pharmacokinetic profile. 17 also robustly stimulated
ERK1/2 phosphorylation in rat cortex and showed highly potent (MED
= 0.16 mg/kg) and efficacious antidepressant-like activity, totally
eliminating immobility in the rat Porsolt test. These data suggest
that the present 5-HT1A receptor-biased agonists could
constitute promising antidepressant drug candidates