AMPA receptor positive allosteric modulators – a case history

Significant advances have been made over recent years in our understanding of the tremendous complexity underlying the function of the human brain, in particular gaining insight into the mechanisms of synaptic plasticity which are key to developmental, adaptive and learning processes. Glutamate, the major excitatory neurotransmitter in the central nervous system (CNS), is of critical importance to these processes, acting at chemical synapses on two major classes of receptors – the metabotropic family of G-protein coupled receptors (mGluRs 1-8), and ionotropic family of ion channel forming receptors (iGluRs). The latter comprises the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainate receptors. Despite similarities shared within this ion channel family, there exist clear structural and pharmacological differences which underlie their individual modes of action. This chapter provides a case history of ion channel lead optimisation, discusses challenges in lead optimisation and selection of clinical discovery candidates, and thoughts on the future of drug discovery programmes