1. Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). In this study we compared a new cyclic antagonist, F-[OPdChaWR], with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a. 2. In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. There were differences in selectivities for the C5aR with F-[OPdChaWR] (pKb 8.64+/-0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16+/-0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19+/-0.38 vs pKb 8.28+/-0.29, respectively) in umbilical artery. This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (-logIC50 values) for C5aR in umbilical artery membranes (F-[OPdChaWR], 7.00+/-0.46; MeFKPdChaWr, 7.23+/-0.17), whereas in PMN membranes the C5aR affinity of the cycle F-[OPdChaWR] (7.05+/-0. 06) was four times higher than that of acyclic MeFKPdChaWr (6.43+/-0. 24, P<0.05). 3. In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. The nature of these differences is yet to be elucidated.