Portal de Periódicos da CAPES

Characterization of the pharmacological profile of the potent LTB 4 antagonist CP‐105,696 on murine LTB 4 receptors in vitro .

1996; Wiley; Volume: 117; Issue: 6 Linguagem: Inglês

10.1111/j.1476-5381.1996.tb16706.x

1476-5381

Henry J. Showell, R Breslow, Maryrose J. Conklyn, Gary P. Hingorani, Kevin M. Koch,

Asthma and respiratory diseases

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.