The activation of the blood borne complement system results in the production of the anaphylatoxin C5a. The interaction of C5a with its receptor leads to activation of inflammatory cells. The inappropriate and excessive production of C5a has been implicated in numerous inflammatory disease states, including arthritis and Alzheimer's disease. At present there are no clinically available compounds to modify the actions of C5a. The aim of this study was to develop antagonists of C5a which could be used in the treatment of inflammatory disease states. This was achieved by the structural modification of the C-terminus of C5a. The C-terminal decapeptide of C5a has been shown to activate the C5a receptor, albeit at a much reduced potency. It was this decapeptide (65ISHKDMQLGR74) which was used as the starting point for drug development. It has been previously shown that an H67F substitution confers a 1000-fold increase in the potency of the C-terminus decapeptide and this substitution has been maintained in all subsequent peptide analogues. In this study amino acid substitutions within the C-terminal peptide were performed to examine the structure-activity relationship of the decapeptide. In particular, substitutions which conferred conformational constraint to the peptide were examined. The conformationally constrained peptide, YSFKPMPLaR, demonstrated increased neutrophil activation and spasmogenic activity, despite failing to display increased binding affinity for the PMN C5a receptor compared to the parent peptide YSFKDMQLGR. C5a is believed to consist of two binding regions which interact with the C5a receptor: the first consists of the loops of its core four-helix bundle, and the second region consists of the C-terminal "tail". In an attempt to increase receptor affinity of the decapeptide (YSFKPMPLaR), the loops of the four-helix bundle were added to the N­ terminus of the decapeptide. The addition of the "loop" sequences led to an increase in receptor affinity and agonist potency. It has been hypothesised that substitution within the C-terminal peptide could result in the loss of agonist activity, and therefore the development of an antagonist. It has since been demonstrated that a peptide containing tryptophan and D-arginine at its C-tenninus is an antagonist of C5a in neutrophils. This motif was also examined in the conformationally constrained peptide, YSFKPMPLaR. The resulting peptide (YSFKPMPLWr) was a full agonist in a spasmogenic assay but a partial agonist compared to C5a in its ability to activate neutrophils. This result demonstrated that amino acid substitution within the C-terminal peptide could lead to a loss of efficacy. Continuing with this antagonist motif (Wr), a series of antagonists based on the C5a peptide antagonist, MeFKPdChaWr, was developed. The effect of cyclisation of this peptide was also examined. The most potent antagonist to be characterised in this study was the cyclic peptide, Ac-[OPdChaWR], which inhibited C5a-induced activation of neutrophils, with an IC50 of 10 nM. The antagonists developed from the C-terminal decapeptide of C5a display insurmountable antagonism of both C5a and small decapeptide agonist analogues of C5a. The pharmacophore of the activation site of the C5a receptor developed from this study leads the way for development of a new clinical entity to treat C5a-mediated immunoinflamrnatory disease states.