SAR exploration of the non-imidazole histamine H3 receptor ligand ZEL-H16 reveals potent inverse agonism

Abstract

Histamine H₃ receptor (H₃ R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 (1) has been reported previously as a high-affinity non-imidazole H₃ R (partial) agonist. Our structure-activity relationship analysis using derivatives of 1 identified both basic moieties as key interaction motifs and the distance of these from the central core as a determinant for H₃ R affinity. However, in spite of the reported H₃ R (partial) agonism, in our hands, 1 acts as an inverse agonist for Gα_i signaling in a CRE-luciferase reporter gene assay and using an H₃ R conformational sensor. Inverse agonism was also observed for all of the synthesized derivatives of 1. Docking studies and molecular dynamics simulations suggest ionic interactions/hydrogen bonds to H₃ R residues D114^3.32 and E206^5.46 as essential interaction points.

Keywords: G protein-coupled receptor (GPCR); agonism; histamine H3 receptor; inverse agonism; non-imidazole.