Dataset Information

Exploring the Effect of Cyclization of Histamine H₁ Receptor Antagonists on Ligand Binding Kinetics.

ABSTRACT: There is an increasing interest in guiding hit optimization by considering the target binding kinetics of ligands. However, compared to conventional structure-activity relationships, structure-kinetics relationships have not been as thoroughly explored, even for well-studied archetypical drug targets such as the histamine H₁ receptor (H₁R), a member of the family A G-protein coupled receptor. In this study, we show that the binding kinetics of H₁R antagonists at the H₁R is dependent on the cyclicity of both the aromatic head group and the amine moiety of H₁R ligands, the chemotypes that are characteristic for the first-generation H₁R antagonists. Fusing the two aromatic rings of H₁R ligands into one tricyclic aromatic head group prolongs the H₁R residence time for benchmark H₁R ligands as well as for tailored synthetic analogues. The effect of constraining the aromatic rings and the basic amines is systematically explored, leading to a coherent series and detailed discussions of structure-kinetics relationships. This study shows that cyclicity has a pronounced effect on the binding kinetics.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8154229 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

Exploring the Effect of Cyclization of Histamine H1 Receptor Antagonists on Ligand Binding Kinetics.

Wang Zhiyong Z Bosma Reggie R Kuhne Sebastiaan S van den Bor Jelle J Garabitian Wrej W Vischer Henry F HF Wijtmans Maikel M Leurs Rob R de Esch Iwan J P IJP

ACS omega 20210507 19

There is an increasing interest in guiding hit optimization by considering the target binding kinetics of ligands. However, compared to conventional structure-activity relationships, structure-kinetics relationships have not been as thoroughly explored, even for well-studied archetypical drug targets such as the histamine H1 receptor (H1R), a member of the family A G-protein coupled receptor. In this study, we show that the binding kinetics of H1R antagonists at ...[more]

PMID: 34056427

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Project description:The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased Ki in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower Ki than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

Dataset Information

Exploring the Effect of Cyclization of Histamine H₁ Receptor Antagonists on Ligand Binding Kinetics.

Publications

Exploring the Effect of Cyclization of Histamine H<sub>1</sub> Receptor Antagonists on Ligand Binding Kinetics.

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