Molecular pharmacological characterisation of recombinant and native NR2B- and NR3B- containing NMDA receptors

Abstract

NMDA receptors are ionotropic, glutamate receptors which mediate fast excitatory transmissions within the central nervous system. They form tetrameric or pentameric heterologous complexes from seven NMDA receptor subunits NRl, NR2A-D and NR3A-B which each convey distinct expression patterns, functional and pharmacological properties to the receptor complex. Due to its involvement in excitatory transmission, over-excitation of the NMDA receptor, particularly the NR2B subunit, has been the focus of pharmaceutical therapeutic targeting for neurodegenerative conditions and chronic pain. This thesis discusses the potential importance and clinical effectiveness of targeting NMDA receptors and the difficulties in drag development arising from the receptor's heteromeric nature. The work herein focuses on the pharmacological characterisation of two novel NR2B-selective antagonists Compound A and Compound B， the physiological and pharmacological effects of NR3 subunit inclusion in the NMDA receptor complex, and the modifications of NMDA receptor physiology and subunit expression during chronic pain states. This research provides novel evidence to suggest that Compound A and Compound В bind with a high selectivity and affinity towards NR1/NR2B containing receptors. It provides novel evidence for a differential cytoprotective effect of the NR3 subunits showing significant cytoprotection in NR1/NR2B, but not NR1/NR2A, receptors and shows that NR3B inclusion in the receptor can differentially modulate the binding affinities ofNR2B-selective antagonists. This study also shows evidence for increased activity of spinal and supra-spinal NR2B-containmg receptors indicating NMDA receptor modulation and involvement in a chronic pain model.