Conformationally restricted formyl methionyl tripeptide chemoattractants: a three-dimensional structure-activity study of analogs incorporating a C ^α,α-dialkylated glycine at position 2

Abstract

The conformationally restricted CHO-L-Met-Xxx-L-Phe-OY (where Xxx = Aib, Ac₃c, Ac₅c, Ac₆c, and Ac₇c; Y = H, Me) tripeptides, analogs of the chemoattractant CHO-L-Met-L-Leu-L-Phe-OH, have been synthesized in solution by classical methods and fully characterized. Compounds were compared to determine the combined effect of backbone conformational preferences and side-chain bulkiness on the relation of three-dimensional structure to biological activity. Each peptide was tested for its ability to induce granule enzyme secretion from rabbit peritoneal polymorphonuclear leukocytes. In parallel, a conformational analysis on the CHO-blocked peptide and their tertbutyloxycarbonylated synthetic precursors was performed in the crystal state and in solution using X-ray diffraction, infrared absorption, and 1H nuclear magnetic resonance. The biological and conformational data are discussed in relation to the proposed model of the chemotactic peptide receptor of rabbit neutrophils.