PT  - JOURNAL ARTICLE
AU  - de Kruijf, Petra
AU  - van Heteren, Jane
AU  - Lim, Herman D.
AU  - Conti, Paolo G.M.
AU  - van der Lee, Miranda M. C.
AU  - Bosch, Leontien
AU  - Ho, Koc-Kan
AU  - Auld, Douglas
AU  - Ohlmeyer, Michael
AU  - Smit, Martin J.
AU  - Wijkmans, Jac C. H. M.
AU  - Zaman, Guido J.R.
AU  - Smit, Martine J.
AU  - Leurs, Rob
TI  - Nonpeptidergic Allosteric Antagonists Differentially Bind to the CXCR2 Chemokine Receptor
AID  - 10.1124/jpet.108.148387
DP  - 2009 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 783--790
VI  - 329
IP  - 2
4099  - http://jpet.aspetjournals.org/content/329/2/783.short
4100  - http://jpet.aspetjournals.org/content/329/2/783.full
SO  - J Pharmacol Exp Ther2009 May 01; 329
AB  - The chemokine receptor CXCR2 is involved in different inflammatory diseases, like chronic obstructive pulmonary disease, psoriasis, rheumatoid arthritis, and ulcerative colitis; therefore, it is considered an attractive drug target. Different classes of small CXCR2 antagonists have been developed. In this study, we selected seven CXCR2 antagonists from the diarylurea, imidazolylpyrimide, and thiazolopyrimidine class and studied their mechanisms of action at human CXCR2. All compounds are able to displace 125I-CXCL8 and inhibit CXCL8-induced β-arrestin2 recruitment. Detailed studies with representatives of each class showed that these compounds displace and antagonize CXCL8, most probably via a noncompetitive, allosteric mechanism. In addition, we radiolabeled the high-affinity CXCR2 antagonist SB265610 [1-(2-bromophenyl)-3-(4-cyano-1H-benzo[d] [1,2,3]-triazol-7-yl)urea] and subjected [3H]SB265610 to a detailed analysis. The binding of this radioligand was saturable and reversible. Using [3H]SB265610, we found that compounds of the different chemical classes bind to distinct binding sites. Hence, the use of a radiolabeled low-molecular weight CXCR2 antagonist serves as a tool to investigate the different binding sites of CXCR2 antagonists in more detail. The American Society for Pharmacology and Experimental Therapeutics