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

Abstract

Histamine H3 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 Gαi 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 D1143.32 and E2065.46 as essential interaction points.

Why Search for Alternative GPCR Agonists?

“…Inverse agonists are orthosteric ligands exhibiting the opposite effect of the agonist. For instance, while the binding affinity of ZEL-H16 is in the same range as histamine for H 3 receptor, this non-imidazole compound induces a dose dependent reduction of H 3 activation on HEK293T cells as measured by a CRE-driven luciferase reporter gene assay [110]. Other examples can be found in the literature, like inverse agonists of melatonin receptors [111], or SR48692 for neurotensin receptor 1 [112] among many others [113].…”