Coumarinyl pyranopyrimidines as new neuropeptide S receptor antagonists; design, synthesis, homology and molecular docking

Abstract

In this work, we described the design, synthesis and characterization of a new class of NPSR antagonists bearing the tetracyclic coumarinyl pyranopyrimidine scaffold incorporated with different acyclic and/or heterocyclic moieties. These compounds are highlighted in this study as never being used as NPSR antagonists before which provides a model for the discovery of new bioactive inhibitors that may hold potential for drug development towards anxiety, food, and addiction disorders. Synthetic and medicinal chemistry studies led to the identification of four potent antagonists, compounds 7d, 10, 12 and 13, which were able to significantly inhibit the stimulatory effect of NPS through counteracting the increased intracellular Ca²⁺ accumulation. The target compound 7d was the most active derivative behaving as a pure NPSR antagonist and displaying IC₅₀ value of 2 μM. Homology model of NPSR was built based on bovine rhodopsin structure. Modeling studies were carried out to further rationalize the NPSR binding mode of the target compounds. Moreover, molecular dynamics simulation study was performed for compounds 7d, 10 and 12 which revealed the stability of the ligand-protein complex and the reliability of the docking studies.

Keywords: Coumarin; Homology; Molecular docking; Molecular dynamics; NPSR; Pyranopyrimidine.