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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 12, 2008; DOI: 10.1124/jpet.107.134783

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Received for publication November 28, 2007.
Revised February 11, 2008.
Accepted for publication February 11, 2008.

Non-competitive antagonism and inverse agonism as mechanism of action of non-peptidergic antagonists at primate and rodent CXCR3 chemokine receptors

Dennis Verzijl 1, Stefania Storelli 1, Danny J Scholten 1, Leontien Bosch 1, Todd A Reinhart 2, Daniel N Streblow 3, Cornelis P Tensen 4, Carlos P Fitzsimons 1, Guido J.R. Zaman 5, James E Pease 6, Iwan J.P. de Esch 1, Martine J. Smit 1, Rob Leurs 1*

1 Vrije Universiteit Amsterdam 2 University of Pittsburgh 3 Oregon Health and Science University 4 Leiden University Medical Center 5 N.V. Organon 6 Imperial College London

* Address correspondence to: E-mail: r.leurs{at}few.vu.nl

Abstract

The chemokine receptor CXCR3 is involved in various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis and allograft rejection in transplantation patients. The CXCR3 ligands CXCL9, CXCL10 and CXCL11 are expressed at sites of inflammation and attract CXCR3-bearing lymphocytes, thus contributing to the inflammatory process. Here, we characterize 5 non-peptidergic compounds of different chemical classes that block the action of CXCL10 and CXCL11 at the human CXCR3, i.e. the 3H-pyrido[2,3-d]pyrimidin-4-one derivatives VUF10472/NBI-74330 and VUF10085/AMG-487, the 3H-quinazolin-4-one VUF5834, the imidazolium compound VUF10132 and the quaternary ammonium anilide TAK-779. In order to understand the action of these CXCR3 antagonists in various animal models of disease, the compounds were also tested at rat and mouse CXCR3, as well as at CXCR3 from rhesus macaque, cloned and characterized for the first time in this study. Except for TAK-779, all compounds show slightly lower affinity for rodent CXCR3 than for primate CXCR3. Additionally, we have characterized the molecular mechanism of action of the various antagonists at the human CXCR3 receptor. All tested compounds act as non-competitive antagonists at CXCR3. Moreover, this non-competitive behavior is accompanied by inverse agonistic properties of all 5 compounds as determined on an identified constitutively active mutant of CXCR3, CXCR3 N3.35A. Interestingly, all compounds except TAK-779 act as full inverse agonists at CXCR3 N3.35A. TAK-779 shows weak partial inverse agonism at CXCR3 N3.35A, and likely has a different mode of interaction with CXCR3 than the other two classes of small molecule inverse agonists.


Key words: CXCR3, antagonist, chemokine, constitutively active mutant, inverse agonist, non-competitive antagonism




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