New quinolone derivatives as neuropeptide S receptor antagonists: Design, synthesis, homology modeling, dynamic simulations and modulation of Gq/Gs signaling pathways

[Display omitted] •New quinolinyl pyranopyrimidines were synthesized as NPSR antagonists.•Compound 10 was significant ligand against Ca+2 mobilization.•Compound 4b was a promising dual ligand towards Ca+2 and cAMP signaling.•Cys197 and Tyr310 were important residues for the NPSR modulation.•MD simulations evaluated the binding stability of compound 10 over 20 ns. In a search for new neuropeptide S receptor antagonists, we have described a new series of quinolone-pyranopyrimidine hybrid derivatives aiming to modify the inhibitory characters towards NPSR to develop new therapeutic strategies against anxiety, addiction and food disorders. We identified six potent antagonists 3, 4b, 6, 8, 9 and 10 which counteracted the stimulatory effect of NPS at both Gq and Gs pathways, at low micromolar concentrations, through modulation of Ca2+ and cAMP signaling, respectively. Molecular docking predicted the orientation mode of the top active compounds; 10 and 4b with ΔG value of –23.94 and –23.87 kcal/mol, respectively that is considered good when compared to that of the reference compound ML154 (ΔG = −25.75 kcal/mol) . Molecular dynamic simulations confirmed the stability of binding of compound 10 to the homology model of NPSR as it reached the equilibrium after 4 ns at RMSD of 1.00 Å while ML154 was faster to achieve the equilibrium after 2 ns at RMSD of 1.00 Å.