Development of GluK2 selective kainate receptor antagonists and investigations into the roles of the NMDA receptor subunit GluN2D in hippocampal synaptic plasticity

Abstract

Novel compounds related to kynurenic acid were synthesised in-house and were pharmacologically characterised with the aim of developing novel GluK2 subunit-selective antagonists. Compounds with relative selectivity on GluN2A, GluN2B and GluN2D subunits of NMDA receptors and GluN2D genetic knockout mice were used to characterise the physiological roles of GluN2D-containing NMDA receptors. Derivatives of kynurenic acid were tested on GluK1, GluK2 and GluA1 homomeric receptors expressed on HEK293 cells using a calcium fluorescence assay, and on f-EPSP recordings from the CA1 subregion of the hippocampus with the aim to develop novel GluK2 antagonists with GluK2 over AMPAR and GluK2 over GluK1 selectivity. Substitutions were made on the 6-position to develop 6-ethylkynurenic acid (UBP2054), which has a GluK2 Ki of 54.0 ± 10.9 μM and estimated IC50 values of > 1 mM and > 2 mM on GluK1 and GluA1, respectively. UBP2054 has an IC50 of > 300 μM for inhibiting AMPAR-mediated f-EPSPs from the CA1 subregion of the hippocampus. Molecular modelling was used to rationalise the pharmacological profile observed in the functional assays. Physiological investigations of GluN2D receptors revealed that the GluN2D NMDAR subunit mediates the induction of LTP in hippocampal Schaffer collateral to CA1 pyramidal cell synapses.

Date of Award	28 Nov 2019
Original language	English
Awarding Institution	The University of Bristol
Supervisor	David Jane (Supervisor) & Stafford L Lightman (Supervisor)