Discovery of Novel, Potent and Selective Glycine Receptor Modulators from Southern Australian Sponges

! i! Consisting of five subunits (!1-!4 and "), glycine receptors (GlyRs) orchestrate inhibitory neurotransmission in the central nervous system (CNS). Mutation and/or dysfunction of different GlyR subunits are associated with CNS diseases such as spasticity and movement disorders (GlyR!1), hyperekplexia (GlyR!1, GlyR!2 and GlyR"), epilepsy (GlyR!2 and GlyR!3) and inflammatory pain (GlyR!1 and GlyR!3). In particular, GlyR!3 has recently emerged as the target of choice for the treatment of chronic inflammatory pain due to its discrete distribution at the lamina II dorsal horn spinal cord, the pain terminal. Unfortunately, while known GlyR modulators lack specificity for GlyRs, that render them undrugable, little is known about GlyR modulators from marine natural products (MNPs), despite the important roles of MNPs in drug discovery programs. Together with the biomedical potential of MNPs and the unmet medical needs in treatment of CNS diseases, recent advances in spectroscopic and ion channel technologies strongly suggest the importance of MNPs in the discovery of novel, potent and specific GlyR modulators. Consequently, chapter 1 discusses the various potential medical benefits of GlyRs and/or MNPs i