Pharmacological characterization of antagonists of the C5a receptor

1 Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukoc ytes (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 th eir inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombin ant 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] (pK(b) 8.64+/-0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16+/-0.11, P<0.05) in PMNs, but o f similar potency (pK(b) 8.19+/-0.38 vs pK(b) 5.28+/-0.29 respectively) in umbilical artery. This trend was also reflected in their relative binding a ffinities, both antagonists having similar affinities (-logIC(50) values) f or C5aR in umbilical artery membranes (F-[OPdChaWR], 7.00+/-0.46; MeFKPdCha Wr, 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 MeFRP dChaWr (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 di fferences in relative receptor binding affinities and antagonistic potencie s against C5a are consistent with differences in receptors within these cel l types. The nature of these differences is yet to be elucidated.