SAR exploration of the non-imidazole histamine H 3 receptor ligand ZEL-H16 reveals potent inverse agonism.

Histamine H 3 receptor (H 3 R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 (1) has been reported previously as a high-affinity non-imidazole H 3 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 H 3 R affinity. However, in spite of the reported H 3 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 H 3 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 H 3 R residues D114 3.32 and E206 5.46 as essential interaction points.