title: Nonpeptidergic allosteric antagonists differentially bind to the CXCR2 chemokine receptor.
abstract: 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.
authors.affiliation: Leiden/Amsterdam Center of Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: de Kruijf
authors.forename: Jane
authors.initials: J
authors.lastname: van Heteren
authors.forename: Herman D
authors.initials: HD
authors.lastname: Lim
authors.forename: Paolo G M
authors.initials: PG
authors.lastname: Conti
authors.forename: Miranda M C
authors.initials: MM
authors.lastname: van der Lee
authors.forename: Leontien
authors.initials: L
authors.lastname: Bosch
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
authors.forename: Douglas
authors.initials: D
authors.lastname: Auld
authors.forename: Michael
authors.initials: M
authors.lastname: Ohlmeyer
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Jac C H M
authors.initials: JC
authors.lastname: Wijkmans
authors.forename: Guido J R
authors.initials: GJ
authors.lastname: Zaman
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: 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
chemical_list: D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B