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

Histamine H-3 receptor (H3R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 (1) has been reported previously as a high-affinity non-imidazole H3R (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 H3R affinity. However, in spite of the reported H3R (partial) agonism, in our hands, 1 acts as an inverse agonist for G alpha(i) signaling in a CRE-luciferase reporter gene assay and using an H3R 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 H3R residues D114(3.32) and E206(5.46) as essential interaction points.

Automated summary

In this study, the structure-activity relationship analysis of derivatives of ZEL-H16 revealed that both basic moieties and their distance from the central core are essential for H3R affinity. However, contrary to previous reports, ZEL-H16 and its derivatives were found to act as inverse agonists for G alpha(i) signaling in this study. Docking studies and molecular dynamics simulations identified ionic interactions/hydrogen bonds as crucial interaction points with H3R residues D114 and E206.