Phe-D-Leu-Phe-D-Leu-Phe derivatives as formylpeptide receptor antagonists in human neutrophils: cellular and conformational aspects

We synthesized several Phe-D-Leu-Phe-D-Leu-Phe analogues in which tert-buty loxycarbonyl and four different ureido substituents were included at the N- terminal of the peptides, obtained as free acid and methyl-ester derivative s. Their biological action was analysed on human neutrophil responses induc ed by iV-formyl-Met-Leu-Phe (fMLF). Several in vitro assays were carried ou t: receptor binding, measurement of Ca2+ intracellular concentration, chemo taxis, superoxide anion production and enzyme release. A conformational inv estigation, using infrared absorption and circular dichroism, was also perf ormed. Our results demonstrate that the compounds examined prefer an ordere d conformation (beta-turn) in amphipathic environment, and are able to anta gonize the neutrophil functions evoked by fMLF. Moreover, the extent of inh ibition of Ca2+ intracellular enhancement, as well as of superoxide anion p roduction and granule enzyme release, appears related to their affinity tow ard the formylpeptide receptor. The free acid peptide derivatives appear to be more active antagonists than the methyl-ester ones. (C) 1999 Elsevier S cience B.V. All rights reserved.