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. 2020 Nov 12;63(21):13090-13102.
doi: 10.1021/acs.jmedchem.0c01494. Epub 2020 Oct 27.

Discovery of a G Protein-Biased Radioligand for the Histamine H2 Receptor with Reversible Binding Properties

Katharina Tropmann  1 , Carina Höring  1 , Nicole Plank  1 , Steffen Pockes  1
Affiliations

Discovery of a G Protein-Biased Radioligand for the Histamine H2 Receptor with Reversible Binding Properties

Katharina Tropmann et al. J Med Chem. .

Abstract

Currently employed histamine H2 receptor (H2R) radioligands possess several drawbacks, for example, high non-specificity, insurmountable binding, or short half-life. We report the synthesis and the chemical and pharmacological characterization of the highly stable carbamoylguanidine-type radioligand [3H]UR-KAT479 ([3H]23), a subtype selective histamine H2 receptor G protein-biased agonist. [3H]23 was characterized by saturation, kinetic, and competition binding assays at the human, guinea pig, and mouse H2 receptors (co-)expressed in HEK293(T) cells. [3H]23 reversibly bound to the respective H2Rs with moderate to high affinity (human/guinea pig/mouse Kd: 24/28/94 nM). In order to investigate the applicability of carbamoylguanidine-type ligands in animal studies elucidating the role of the H2R in the brain, we performed a preliminary partitioning experiment in the whole human/mouse blood, which indicated a low binding of [3H]23 to red blood cells. These properties turn [3H]23 into a powerful tool for the determination of binding affinities and demonstrate the promising pharmacokinetic profile of carbamoylguanidine-type ligands.

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