Structure–activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor Original Research Article

Prompted by our interest in neuroprotective agents with multiple mechanisms of action, we assessed the structure–activity relationship of a series of pentacycloundecylamine derivatives previously shown to have both L-type calcium channel blocking activity and N-methyl-d-aspartate receptor (NMDAR) antagonistic activity. We utilized a functional assay to measure NMDAR channel block using 45Ca2+ influx into synaptoneurosomes. The cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.02,6. 03,10.05,9]undecane (NPG1-01) proved to be the most potent experimental compound with an IC50 of 2.98 μM, while 8-amino-pentacyclo[5.4.0.02,6.03,10.05,9]undecane had the next most potent IC50 of 4.06 μM. Increasing the polycyclic cage size of NGP1-01 from a pentacycloundecane to a tridecane cage structure, but retaining the N-benzyl moiety decreased potency 10-fold, indicating a limitation on the volume of the cage that can be accommodated in the channel binding site. In the presence of NGP1-01, NMDA/glycine-induced maximal 45Ca2+ influx was attenuated by 34% with an insignificant effect on agonist potency. These results are consistent with uncompetitive antagonism for this group of compounds. Radioligand binding studies with [3H]MK-801 or [3H]TCP showed little or no displacement of these ligands by pentacycloundecylamines, suggesting that the latter compounds bind to a unique site in the NMDAR channel. The pentacycloundecylamines tested represent a novel group of NMDAR antagonists that have potential as therapeutic agents for neurodegenerative diseases including Parkinson’s and Alzheimer’s disease.