Studies on fMLP-receptor interaction and signal transduction pathway by means of fMLP-OMe selective analogues

Abstract For-Thp-Leu-Ain-OMe ([Thp 1 , Ain 3 ] fMLP-OMe) (2), for-Met-Δ z Leu-Phe-OMe ([Δ z Leu 2 ] fMLP-OMe) (3), for-Thp-Leu-Phe-OMe ([Thp 1 ] fMLP-OMe) (4), and for-Met-Leu-Ain-OMe ([Ain 3 ] fMLP-OMe) (5) are for-Met-Leu-Phe-OMe (fMLP-OMe) (1) analogues which discriminate between different responses of human neutrophils. Peptides 3 and 5, similar to fMLP-OMe, enhance neutrophil cyclic AMP (cAMP) as well as calcium levels, while analogues 2 and 4, which evoke only chemotaxis, do not alter the concentration of these intracellular messengers. When we tested the peptides' ability to displace [ 3 H]-fMLP from its binding sites, the following order of potency was observed: analogue 1 > 3 > 5 > 2 > 4. A particularly low activity at the receptor level characterized analogues 2 and 4. Their low effectiveness was not improved by the addition of cytochalasin B, by different incubation temperatures, or by the absence of endogenous guanine nucleotides, conditions known to influence fMLP receptor fate and functionality. We speculate that, in certain conditions, the fMLP receptor may undergo conformational changes that impede the binding of pure chemoattractants.