The neutrophil leucocyte is a key cell in the body's host- defense mechanism, especially the acute inflammatory response. Mobilization of the neutrophil can be achieved by stimulating a variety of cell surface receptors, including the formyl peptide receptor. While there are numerous, high affinity agonists (10-11M) for this receptor, there are only weak antagonists (10-7 M). This research proposes to expand upon the observation that dimeric and multimeric agonists have enhanced potency (>10 fold) and to prepare a dimeric and multimeric formyl peptide antagonists. These will include symmetrical dimers of the prototype antagonist (Boc- Phe-Leu-Phe-Leu-Phe-OH) coupled through the carboxy terminus or amino side chains of added Lys residues, using appropriate bifunctional linkers; or, through disulfide bond formation using added Cys residues. In addition, multimeric antagonists analogs will be prepared by coupling to inert, multivalent carriers or will be prepared using a multiple antigenic peptide strategy (MAP) technology. All compounds will be evaluated for their ability to bind to the formyl peptide receptor using flow cytometry and to inhibit superoxide formation produced by CHO-Met- Leu-Phe-OH. The development of specific, high affinity antagonists of the formyl peptide receptor could result in the development of a new class of anti-inflammatory drugs which selectively targets the neutrophil leucocyte
