Molecular pharmacology of C3aR modulators

Abstract

The complement system plays key roles in both the innate (non-specific) and acquired (specific) immune response. Complement activation is a tightly regulated process, which takes place in a sequential manner by at least three pathways. All of these pathways generate a small anaphylatoxin protein called C3a. C3a signals immune cells which infiltrate to sites of infection or injury and mount inflammatory responses leading to elimination of pathogens or damaged cells and induction of adaptive immunity. Genetic deficiency of C3 results in susceptibility to bacterial infection. However, in excess C3a can be harmful and catalyses the pathogenesis of many disease conditions. To date, there have been no truly selective and potent C3a receptor agonists/antagonists. Therefore, the purpose of this thesis was to explore the potential to develop a small molecule C3aR agonist/antagonist that can be a useful as a pharmacological probe or biomarker for studying the physiological and pharmacological roles of C3a. Chapter 1 briefly describes basic pharmacology terminology and reviews current knowledge of GPCRs, GPCR intracellular signalling pathways,