Creation of novel bioactive agents on the basis of fragment evolution approach of natural products

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Development of novel ligands, that specifically interact with receptors located at synapses of mammalian nervous system, is important to understand and control complex brain functions at a molecular level. We had synthetically developed IKM-159 as a specific AMPA receptor antagonist, and in the present study, the structure-activity relationships have been extensively studied. As a result, we found that(2R)-IKM159 is neuronally active, whereas the(2S)-isomer is inactive. Furthermore, the interactions with GluA2 subunit have been clarified by X-ray crystallography of(2R)-IKM159 in complex with GluA2 dimer.