SAR exploration of the non-imidazole histamine H3 receptor ligand ZEL-H16 reveals potent inverse agonism.
Arch Pharm (Weinheim)
; 356(1): e2200451, 2023 Jan.
Article
in En
| MEDLINE
| ID: mdl-36310109
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 Gαi 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 D1143.32 and E2065.46 as essential interaction points.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Histamine
/
Receptors, Histamine H3
Language:
En
Journal:
Arch Pharm (Weinheim)
Year:
2023
Document type:
Article
Affiliation country: