Transforming the treatment of schizophrenia: Design & development of AMPA receptor modulators with improved safe profiles as novel drugs for treating the cognitive dysfunction associated with schizophrenia and other CNS disorder

In schizophrenia, existing drugs treat the positive symptoms (e.g. paranoia, auditory hallucinations) but have little effect upon the cognitive deficit (impaired attention, memory and problem-solving) and negative symptoms (lack of motivation and impaired social function) which remain a major barrier to the resumption of a normal life. Accordingly, a drug that improves either or ideally both of these illness dimensions will revolutionize the treatment of schizophrenia. While a dysfunction of dopaminergic neurotransmission in schizophrenia is long established, recent pharmacological and genetic evidence implicates glutamatergic disturbances, more specifically hypofunctioning of NMDA receptors, in the pathophysiology of schizophrenia and in particular the cognition and negative symptom dimensions. The AMPA subtype of glutamate receptor is a partner for NMDA receptors and plays a crucial role in the synaptic plasticity associated with cognition, resulting in the Project hypothesis: Increasing AMPA receptor function will improve cognitive function in schizophrenia. Until recently, the cognitive enhancement resulting from increased AMPA receptor function was thought to be associated with a mechanism-based convulsant liability. However, while at GSK, Prof. Ward demonstrated that is it possible to enhance AMPA receptor function without convulsant activity. It is this innovation that forms the basis of the current proposal. Project goal: To identify a safe, well-tolerated AMPA receptor-modulating drug ready for First-in-Human dosing.