Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 983.36 of the human histamine H4 receptor. (15th August 2013)

• Record Type: Journal Article
• Authors: Nijmeijer, S; Engelhardt, H; Schultes, S; van de, A C; Lusink, V; de, C; Wijtmans, M; Haaksma, E E J; de, I J P; Stachurski, K; Vischer, H F; Leurs, R
• Is Part Of: British journal of pharmacology. Volume 170:Number 1(2013:Sep.)
• Page Start: 89
• Page End: 100
• Publication Date: 2013-08-15
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12113
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12113-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The recently proposed binding mode of 2‐aminopyrimidines to the human (h) histamine H<sub>4</sub> receptor suggests that the 2‐amino group of these ligands interacts with glutamic acid residue E182<sup>5.46</sup> 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<sup>3.36</sup> in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C98<sup>3.36</sup> 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 H<sub>4</sub> receptor research.</p> </sec> <sec id="bph12113-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We designed and synthesized VUF14480, and pharmacologically characterized this compound in hH<sub>4</sub> 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.</p> </sec> <sec id="bph12113-sec-0003" sec-type="section"> <title>Key Results</title> <p>VUF14480 was shown to be a partial agonist of hH<sub>4</sub> receptor‐mediated G protein signalling and β‐arrestin2 recruitment. VUF14480 bound covalently to the hH<sub>4</sub> receptor with submicromolar affinity. Serine substitution of C98<sup>3.36</sup> prevented this covalent interaction.</p> </sec> <sec id="bph12113-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>VUF14480 is thought to bind covalently to the hH<sub>4</sub> receptor‐C98<sup>3.36</sup> residue and partially induce hH<sub>4</sub> 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 hH<sub>4</sub> receptor.</p> </sec> <sec id="bph12113-sec-1001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue‐1</p> </sec> </abstract>