The AMPA receptor subtype of ionotropic glutamate receptors is responsible for mediating the majority of fast, excitatory signalling within the central nervous system.  Re-instating full glutamatergic function by positive modulation of AMPA receptors could address the hypoglutamatergic state underling the symptoms of many disease states, including schizophrenia.A number of chemically diverse AMPA receptor positive modulators have been identified that have reached Phase II clinical trials.  As yet though, none has successfully progressed further.  This presentation outlines work to identify a chemically distinct series of AMPAR positive modulators which addresses the difficulties created by heterogeneous AMPA receptor populations and the development of structure activity relationships driven by homomeric, recombinant systems on high throughput platforms. In particular, a description will be given of the role played by X-ray crystallography in guiding selection and prioritisation of targets through the lead optimisation process, ultimately delivering a novel drug candidate for clinical evaluation.

AMPA receptor modulators: Improving the concept to get to the clinic

244th National Meeting (2012)

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