Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor.

Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, Rootstown, OH 44272-0095, USA.
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 (45)Ca(2+) influx into synaptoneurosomes. The cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6). 0(3,10).0(5,9)]undecane (NPG1-01) proved to be the most potent experimental compound with an IC(50) of 2.98microM, while 8-amino-pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane had the next most potent IC(50) of 4.06microM. 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 (45)Ca(2+) 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 [(3)H]MK-801 or [(3)H]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.
Mesh Terms:
Amines, Animals, Brain, Dizocilpine Maleate, Excitatory Amino Acid Antagonists, Ion Channels, Male, Mice, Mice, Inbred ICR, Models, Molecular, Phencyclidine, Piperidines, Radioligand Assay, Receptors, N-Methyl-D-Aspartate, Structure-Activity Relationship, Synaptosomes, Thiophenes
Bioorg. Med. Chem. Feb. 01, 2007; 15(3);1525-32 [PUBMED:17157509]
181478
Switch View:
  • Chemicals (1)