The complement system is an integral component of the innate immune response to infection and injury. The anaphylatoxins, C3a and C5a, are produced upon activation of the classical, alternative or mannan-binding lectin complement pathways. C5a is a potent pro-inflammatory mediator and overactivation or underegulation of C5a is implicated in the pathogenesis of numerous acute and chronic immune and inflammatory diseases. A narrower range of pro-inflammatory activities are attributed to C3a. However, C3a-mediated anti-inflammatory actions and emerging physiological roles e.g. peripheral stem cell mobilisation, indicate that C3a has a larger role in physiology and pathophysiology than previously considered.Unravelling the role of C3a in physiology and disease has been hampered by a dearth of small molecule C3a receptor (C3aR) selective agonists and antagonists. In 2001, a novel non-peptide C3aR antagonist (C3aRA), with activity in vitro and in vivo, was reported. The pharmacology of this compound has been the focus of much of the present study. We confirm that the C3aRA does antagonise C3aRs in vitro and in vivo. However, the C3aRA induces moderate neutropaenia and high dose, transient, blood pressure elevation, actions that are not associated with antagonism of C3aRs. Intriguingly, the C3aRA-induced neutropaenia is partially inhibited by a selective C5a receptor antagonist. However, at this stage we can only speculate on the mechanisms of these ancillary effects making it difficult to accurately interpret the results of animal model studies.We have revealed that the anti-inflammatory effects of the C3aRA in an animal model of gastrointestinal ischemia/reperfusion injury diminish if reperfusion is carried out after the neutropenic effects of the C3aRA have subsided, but whilst the C3aR blockade remains. This indicates a clear dissociation between the receptor blocking effects of the antagonist and antiinflammatory activity in this model of ischemia/reperfusion injury, which we attribute to the transient global sequestration of circulating neutrophils induced by the C3aRA.C3aR blockade did not protect rats from endotoxic shock and the C3aRA actually potentiated elevation of TNF-a concentrations and augmented the drop in circulating neutrophil numbers induced by infusion of lipopolysaccharide. These results may indicate an anti-inflammatory role for C3a in endotoxic shock and as such are consistent with a previous study that indicated that C3aR deficiency exacerbated murine endotoxic shock.In light of the limitations of the small molecule C3aRA uncovered in this study, the need for selective, stable and potent small molecule C3aR agonists and antagonists for research and preclinical development remained unmet. We approached the development of C3aR ligands from several perspectives with the initial aim of separating C3aR affinity from C5aR affinity in linear peptide analogues of anaphylatoxin C-terminal sequences. Though preliminary, our development program generated a linear decapeptide, YSFKDMP(Me-L)aR (EP-67) with high affinity and selectivity for C3aRs and a series of linear hexapeptides, related to FKPLaR, with moderate C3aR affinity. Crucially, both peptides were essentially completely selective for C3aRs over C5aRs. Initial efforts to introduce global constraints into linear peptides proved successful and this program generated a cyclic octapeptide with reasonable C3aR affinity and essentially complete C3aR selectivity. Although this cyclic peptide has not been optimised for C3aR affinity and activity this compound represents a significant advance towards the development of C3aR ligands as lead candidates for clinical development.