Sussex Drug Discovery Centre (SDDC)

Central Nervous System Diseases

Despite the huge societal burden of central nervous system (CNS) disorders, many pharmaceutical companies are decreasing their efforts within neuroscience due to the inherent challenges of delivering new medicines. However, there is little doubt that there remains a huge unmet medical need for the treatment of diseases of the CNS. The total of the direct and indirect costs of mental health problems within the EU has been estimated at around £800 billion.

Our approach is to establish a portfolio of neuroscience targets that will help retain within the UK knowledge of and expertise in neuroscience drug discovery that would otherwise be lost at a time when society needs it most.

Growing need for new neuroscience medicines

Over the last 5 years or so, the UK has been particularly affected with the closures of many major pharmaceutical neuroscience drug discovery sites resulting in the loss of over 1000 jobs. We are currently seeking to develop cognition enhancing drugs to alleviate some of the burden on society, particularly in regard to Alzheimer’s disease, Huntingdon’s disease and schizophrenia. Over the last decade or so, it has become increasingly appreciated that one of the primary causes of disability in psychiatric disorders are cognitive deficits with, for example, the focus in schizophrenia shifting from the control of psychotic symptoms to attempts to understand and treat the negative symptoms, such as cognitive impairment that prevent patients from resuming a fully productive life (Insel et al., 2013).

Focus on the synapse in CNS disorders

Within the CNS, information is transferred from nerve cell to nerve cell via the synapse. At the synapse, an action potential arrives at the presynaptic nerve terminal and neurotransmitter is released, diffuses across the gap between the pre- and postsynaptic membranes and then interacts with the appropriate receptor on the postsynaptic membrane. The seminal work of Seth Grant and colleagues based around a proteomic analysis of proteins associated with the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the postsynaptic density defined the postsynaptic receptor as a component of a highly complex structure containing 77 proteins (see Figure 1).

Figure 1. Modified from Emes, R.D. and Grant, S.G.N. (2012) Evolution of synapse complexity and diversity. Annu. Rev. Neurosci., 35:111-31

These studies of the postsynaptic density proteome has been further extended to show that there are 200 gene mutations associated with 133 brain diseases; the so-called synaptopathies. The synaptosome provides the conceptual framework for the convergence of multiple genetic factors associated with specific disorders, such as schizophrenia (Figure 2 ). Although the synapses associated with excitatory glutamate neurotransmission are the best characterised, a similar complexity is shared by the inhibitory synapses associated with GABAergic neurotransmission.

Figure 2. Taken from Hall, J., Trent, S., Thomas, K.L., O'Donovan, M.C. and Owen, M.J. (2015) Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity. Biol. Psychiatry, 77:52-8

Ion channels play a key role in synaptic function and dysfunction

The activation of ion channels provide a rapid response, whether they be, for example, voltage-gated ion channels that mediate the flux of calcium ions or GABAA receptors (GABAAR) or ionotropic glutamate receptors (iGluR) that mediate the majority of inhibitory and excitatory neurotransmission within the CNS, respectively. Mutations in these receptors are associated with a variety of disorders that represent the so-called channelopathies with, for example, mutations in the GABAA receptor often being associated with various forms of epilepsy. In both GABAAR and iGluR receptor families (the latter of which comprise the N-methyl-D-asparate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors), mutations that disrupt protein structure, conformation, abundance, or localization have been described. The importance of ion channels to CNS function and disease is further emphasised by that pharmacological effects produced by drugs that affect certain of these receptor subtypes. For example, barbiturates and benzodiazepines effect GABAAR whereas ketamine acts by attenuating NMDA receptor function.

Ion channel drug discovery

Given their importance within the physiology and pathophysiology of the CNS, it is surprising that ion channel remain a relatively unexploited therapeutic target class. However, most of the currently, clinically-relevant drugs were derived from empirical observations of whole-animal pharmacology (e.g., the benzodiazepines) and the challenge for target-based drug discovery observations has been largely related to the technical issues around resource-intensive electrophysiology assays. However, the advent of medium- to high-throughput electrophysiology has enabled ion channel drug discovery which, coupled to their well-established role in a variety of CNS disorders, has resulted in a resurgence of interest in ion channel drug discovery. Moreover, certain ion channels (e.g., the AMPA receptor) are structurally-enabled (see Figure) which permits insights into drug mechanisms of action that can be used to steer the drug discovery process. Given our target expertise and technical capabilities (electrophysiology, structural biology and medicinal chemistry and chemoinformatics), the Sussex Drug Discovery Centre is therefore ideally positioned to exploit the emerging understanding of ion channel synaptic physiology and pathophysiology to prosecute ion channel drug discovery targets, with our current focus being the GABAAR, iGluR (AMPA, NMDA and kainate) and CaV ion channels

Figure 1. A. Structure of rat GluA2 AMPA receptor. Sobolevsky, A.I., Rosconi, M.P. and Gouaux, E. (2009) X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature, 462:745-56. B. Use of structural information regarding the AMPA receptor to guide medicinal chemistry efforts (Ward, S.E. et al. (2011) Integration of lead optimization with crystallography for a membrane-bound ion channel target: discovery of a new class of AMPA receptor positive allosteric modulators. J. Med. Chem., 54:78-94.