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

• Published in: Archiv der Pharmazie (Weinheim) Vol. 356; no. 1; p. e2200451
• Main Authors: Wágner, Gábor, Mocking, Tamara A M, Ma, Xiaoyuan, Slynko, Inna, Da Costa Pereira, Daniel, Breeuwer, Robin, Rood, Niek J N, van der Horst, Cas, Vischer, Henry F, de Graaf, Chris, de Esch, Iwan J P, Wijtmans, Maikel, Leurs, Rob
• Format: Journal Article
• Language: English
• Published: Germany 01-01-2023
• Subjects: Drug Inverse Agonism; Histamine; Histamine Agonists - chemistry; Histamine Agonists - pharmacology; Ligands; Receptors, Histamine; Receptors, Histamine H3; Structure-Activity Relationship; histamine H3 receptor; G protein-coupled receptor (GPCR); agonism; non-imidazole; inverse agonism
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202200451

Histamine H
receptor (H
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
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
R affinity. However, in spite of the reported H
R (partial) agonism, in our hands, 1 acts as an inverse agonist for Gα
signaling in a CRE-luciferase reporter gene assay and using an H
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
R residues D114
and E206
as essential interaction points.