RT Journal Article
SR Electronic
T1 Nonpeptidergic Allosteric Antagonists Differentially Bind to the CXCR2 Chemokine Receptor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 783
OP 790
DO 10.1124/jpet.108.148387
VO 329
IS 2
A1 Petra de Kruijf
A1 Jane van Heteren
A1 Herman D. Lim
A1 Paolo G.M. Conti
A1 Miranda M. C. van der Lee
A1 Leontien Bosch
A1 Koc-Kan Ho
A1 Douglas Auld
A1 Michael Ohlmeyer
A1 Martin J. Smit
A1 Jac C. H. M. Wijkmans
A1 Guido J.R. Zaman
A1 Martine J. Smit
A1 Rob Leurs
YR 2009
UL http://jpet.aspetjournals.org/content/329/2/783.abstract
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