Nonpeptidergic allosteric antagonists differentially bind to the CXCR2 chemokine receptor.
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 (125)I-CXCL8 and inhibit CXCL8-induced beta-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 [(3)H]SB265610 to a detailed analysis. The binding of this radioligand was saturable and reversible. Using [(3)H]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.
de Kruijf
Petra
P
Leiden/Amsterdam Center of Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
van Heteren
Jane
J
Lim
Herman D
HD
Conti
Paolo G M
PG
van der Lee
Miranda M C
MM
Bosch
Leontien
L
Ho
Koc-Kan
KK
Auld
Douglas
D
Ohlmeyer
Michael
M
Smit
Martin J
MJ
Wijkmans
Jac C H M
JC
Zaman
Guido J R
GJ
Smit
Martine J
MJ
Leurs
Rob
R
D000495:Allosteric Site; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011869:Radioligand Assay; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014162:Transfection
D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B