SAR exploration of the non-imidazole histamine H3 receptor ligand ZEL-H16 reveals potent inverse agonism.
| Title: | SAR exploration of the non-imidazole histamine H3 receptor ligand ZEL-H16 reveals potent inverse agonism. |
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| Authors: | Wágner G; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Mocking TAM; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Ma X; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Slynko I; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Da Costa Pereira D; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Breeuwer R; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Rood NJN; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; van der Horst C; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Vischer HF; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; de Graaf C; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; de Esch IJP; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Wijtmans M; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Leurs R; Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. |
| Source: | Archiv der Pharmazie [Arch Pharm (Weinheim)] 2023 Jan; Vol. 356 (1), pp. e2200451. Date of Electronic Publication: 2022 Oct 30. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Wiley-VCH Verlag GmbH & Co. KGaA Country of Publication: Germany NLM ID: 0330167 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-4184 (Electronic) Linking ISSN: 03656233 NLM ISO Abbreviation: Arch Pharm (Weinheim) Subsets: MEDLINE |
| Imprint Name(s): | Publication: : Weinheim Germany : Wiley-VCH Verlag GmbH & Co. KGaA; Original Publication: Weinheim, Verlag Chemie GmbH. |
| MeSH Terms: | Histamine* ; Receptors, Histamine H3*; Histamine Agonists/pharmacology ; Histamine Agonists/chemistry ; Drug Inverse Agonism ; Ligands ; Structure-Activity Relationship ; Receptors, Histamine ; Piperidines |
| 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.; (© 2022 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.) |
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| Grant Information: | 201703250074 CSC Chinese scholarship grant; 718.014.002 The Netherlands Organization for Scientific Research (NWO) |
| Contributed Indexing: | Keywords: G protein-coupled receptor (GPCR); agonism; histamine H3 receptor; inverse agonism; non-imidazole |
| Substance Nomenclature: | 820484N8I3 (Histamine); 0 (Ligands); 0 (Histamine Agonists); 0 (Receptors, Histamine H3); 0 (Receptors, Histamine); 0 (ZEL-H16); 0 (Piperidines) |
| Entry Date(s): | Date Created: 20221030 Date Completed: 20230103 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| DOI: | 10.1002/ardp.202200451 |
| PMID: | 36310109 |
| Database: | MEDLINE |
Journal Article