Synthesis and biological evaluation of new ligands designed to selectively interact with kainate receptors

Kainate receptors (KARs) are a family of ionotropic glutamate receptors (iGluRs). KARs are know to play a role in pain, epilepsy, neurodegenerative and psychiatric disorders but the lack of highly selective ligands for KAR subtypes (GluK1-5) prevented so far an exhaustive pharmacological characterization.1 Starting for the natural compound L-tricholomic acid, which is a non-selective AMPA/KA agonist, we designed a series of higher homologues of general structure A, in which the distal acidic group is linked to the isoxazoline ring through an aromatic spacer. Homologation is aimed at switching the profile from agonist to antagonist, by preventing the ligand binding domain closure, whereas an increased selectivity may arise from additional interactions played by the aromatic ring. Similarly, starting from CIP-AS, a non selective AMPA/KA agonist previously developed by our group, we designed a series of higher homologues of general structure B. Moreover, we designed new analogs of general structure C, in which the isoxazoline ring was replaced by a N-substituted- pyrazoline, in order to explore the role played by an additional substituent (e.g. a methyl group) in this position, considering that, due to the presence of less hindered amino acids, KARs are known to accommodate larger substituents than AMPARs. Preliminar biological data will be presented and discussed.