Design and Pharmacological Characterization of VUF14480, a Covalent Partial Agonist That Interacts with Cysteine 98(3.36) of the Human Histamine H₄ Receptor

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2013 Jan 26

PMID 23347159

Citations 12

Authors

S Nijmeijer

H Engelhardt

S Schultes

A C van de Stolpe

V Lusink

C de Graaf

M Wijtmans

E E J Haaksma

I J P de Esch

K Stachurski

H F Vischer

R Leurs

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: The recently proposed binding mode of 2-aminopyrimidines to the human (h) histamine H₄ receptor suggests that the 2-amino group of these ligands interacts with glutamic acid residue E182(5.46) in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2-position of this pyrimidine are also in close proximity to the cysteine residue C98(3.36) in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C98(3.36) by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H4 receptor research.

Experimental Approach: We designed and synthesized VUF14480, and pharmacologically characterized this compound in hH4 receptor radioligand binding, G protein activation and β-arrestin2 recruitment experiments. The ability of VUF14480 to act as a covalent binder was assessed both chemically and pharmacologically.

Key Results: VUF14480 was shown to be a partial agonist of hH4 receptor-mediated G protein signalling and β-arrestin2 recruitment. VUF14480 bound covalently to the hH₄ receptor with submicromolar affinity. Serine substitution of C98(3.36) prevented this covalent interaction.

Conclusion And Implications: VUF14480 is thought to bind covalently to the hH₄ receptor-C98(3.36) residue and partially induce hH₄ receptor-mediated G protein activation and β-arrestin2 recruitment. Moreover, these observations confirm our previously proposed binding mode of 2-aminopyrimidines. VUF14480 will be a useful tool to stabilize the receptor into an active confirmation and further investigate the structure of the active hH₄ receptor.

Citing Articles

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Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR.

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New Chemical Biology Tools for the Histamine Receptor Family.

Zheng Y, Wagner G, Hauwert N, Ma X, Vischer H, Leurs R Curr Top Behav Neurosci. 2022; 59:3-28.

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Differential Role of Serines and Threonines in Intracellular Loop 3 and C-Terminal Tail of the Histamine H Receptor in β-Arrestin and G Protein-Coupled Receptor Kinase Interaction, Internalization, and Signaling.

Verweij E, Al Araaj B, Prabhata W, Prihandoko R, Nijmeijer S, Tobin A ACS Pharmacol Transl Sci. 2020; 3(2):321-333.

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Covalent Inhibition of the Histamine H Receptor.

Wagner G, Mocking T, Kooistra A, Slynko I, Abranyi-Balogh P, Keseru G Molecules. 2019; 24(24).

PMID: 31835873 PMC: 6943558. DOI: 10.3390/molecules24244541.

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