Characterization of the pharmacological profile of the potent LTB4 antagonist CP‐105,696 on murine LTB4 receptors in vitro.

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Abstract
1 Binding of [3H]‐leukotriene B4 ([3H]‐LTB4) to murine spleen membranes (MSM) was determined. 2 Scatchard analyses of [3H]‐LTB4 binding indicated the presence of high (KD1 = 1.7 nM) and low (KD2 = 7.5 nM) affinity receptors on MSM with Bmax. values of 151 fmol mg−1 protein (Bmax1) and 354 fmol mg−1 protein (Bmax2), respectively. 3 CP‐105,696, a potent LTB4 antagonist, inhibited [3H]‐LTB4 (0.67 nM) binding to the high affinity receptor on MSM, IC50 = 30.2 nM, Ki = 17.7 nM with a Hill coefficient of 0.93. 4 Scatchard analyses of [3H]‐LTB4 binding to MSM in the presence of CP‐105,696 indicated that the high‐affinity receptor was inhibited in a non‐competitive manner and the low‐affinity receptor in a competitive manner. 5 Isolated peripheral blood murine neutrophils (MN) responded chemotactically to LTB4, EC50 = 2.5 nM. CP‐105,696 blocked this response, IC50 = 2.3 nM. When examined over a full concentration‐response range of LTB4, CP‐105,696 inhibited chemotaxis in a non‐competitive manner. 6 Murine neutrophils in anticoagulated whole blood upregulated the integrin, complement receptor type 3 (CD11b/CD 18, Mac‐1) in response to LTB4, EC50 = 20 nM and this was inhibited by CP‐105,696 in a competitive manner. 7 These results provide evidence that MSM have specific binding sites for LTB4, and as exemplified by CP‐105,696, that these receptors may be useful for determining the potency and nature of antagonism of novel LTB4 receptor antagonists.

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