N-methyl-D-aspartate (NMDA) and sigma receptor antagonism as neuroprotective strategy for polycyclic amines

Abstract

Polycyclic cage compounds and their effects on different receptors and receptor channels have been studied extensively. It is evident that these compounds may prove to be of great value in future treatment of neurodegenerative diseases. Although many of the mechanisms involved in the process of neurodegeneration are still not fully elucidated, researchers are getting closer to identifying more and new possible targets for drug treatment. In this study the focus was mainly on the effect of polycyclic cage compounds on calcium homeostasis, a key process in neurodegeneration. The role of sigma receptors in calcium homeostasis was also evaluated. As can be seen in the literature, these receptors are an exciting new prospect for drug targeting and treatment of not only neurodegenerative diseases but tumor related illnesses as well. A series of pentacycloundecane derivatives containing sigma bias substituents were selected and synthesised using reductive amination. Their effect on intracellular calcium in synaptoneursomes, were evaluated using fluorescent techniques and their affinity for sigma receptors was determined through a radio ligand binding study on Sprague-Dawley rat liver membranes. The difference between the oxa-and aza derivatives as well as the effect of chain length between the cage and the piperidine moiety on calcium influx and binding affinity were evaluated.