G Protein coupled receptors (GPCRs) represent a large number of drug design targets, with over 1000 such receptors identified in the human body. The diverse structural nature of these receptors, and the absence of three dimensional structures of GPCRs, present significant challenges in drug design. Some of these challenges are addressed in this thesis, using two GPCRs, the C5a receptor and the metabotropic glutamate receptor. Regulation of these receptors has potential therapeutic use.
Chapter One is a general review of G protein-coupled receptors, focussing on structural features, types of receptors and ligands, activation mechanisms, models, and how they have been targeted in drug design.
Chapter Two reports the synthesis of a number of cyclic peptides which act as antagonists of the C5a receptor. The relationship between affinity for the receptor and the size and shape of the various side chains of the cycle are discussed. The resulting structure activity relationships are used in generation of an antagonist pharmacophore using molecular modelling.
Chapter Three reports the investigation of the requirements for agonism of the C5a receptor through synthesis of thirty linear and cyclic peptides. An NMR structure of a linear agonist is also reported.
Chapter Four is a homology modelling study of the C5a receptor and includes generation of a series of models which explain the behaviour of ligand-receptor interaction reported in this thesis and in the literature.
Chapter Five reports homology modelling studies of metabotropic glutamate receptors, and proposes a basis for selectivity between subtypes of these receptors based on the findings of these studies.