Discovery of potent S1R agonist by means of screening campaign and analysis of binding interactions.
According to DFT calculations, the synthesis of spirocyclic σ1 ligands involves two aza-Michael additions or a [4 + 2] cycloaddition. Dispiro ligand with a high number of sp3 C-atoms shows promising σ1 affinity, selectivity and physicochemical properties.
Compound 7 exhibited high σ1R affinity and selectivity and produced a potent antinociceptive effect in a mouse model of inflammatory pain. Molecular modeling studies were performed to analyze its key interactions with σ1R.
The relative configuration and the substitution pattern control the interaction of 2-(2-phenyl1,3-dioxan-4-yl)ethan-1-amines with σ1 receptors or the PCP binding site of NMDA receptors.
The need for suitable in vitro biological membrane models for accurate prediction of in vivo biodisposition of potential drug molecules is critical in early-stage drug discovery science.