Chapter8_6okt_24 pages_FINAL.indd

Binding pocket of small molecular weight antagonists In Chapter 3 [1] we extensively investigated the mechanism of action of antagonists belonging to the diarylurea, thiazolopyrimidine and imidazolylpyrimidine chemical classes. All antagonists antagonize CXCL8 most probably via a non-competitive, allosteric mechanism. Interestingly, using the diarylurea [3H]-SB265610 compound, we discovered that CXCR2 antagonists of different chemical classes bind to distinct binding sites at the CXCR2 receptor. Recently, two research groups provided evidence that compounds belonging to the diarylurea and thiazolopyrimidine class most likely bind to the intracellular region of CXCR2 [2, 3]. This is an interesting finding, since small molecular weight antagonists are mostly considered to bind to the 7 trans-membrane (TM) domain of chemokine receptors [4], including repertaxin to CXCR1 [5, 6], AMD3100 to CXCR4 [7, 8] , BX-471 to CCR1 [9], TAK-779 to CCR2 /CCR5 [10-14] and Maraviroc to CCR5 [14].