Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor.
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Geldenhuys WJ, Malan SF, Bloomquist JR, Van der Schyf CJ
Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor.
Bioorg Med Chem. 2007 Feb 1;15(3):1525-32. Epub 2006 Sep 29.
- PubMed ID
- 17157509 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Tenocyclidine Glutamate receptor ionotropic, NMDA 2A Protein Humans YesAntagonistDetails Tenocyclidine Glutamate receptor ionotropic, NMDA 3A Protein Humans YesAntagonistDetails Tenocyclidine Glutamate receptor ionotropic, NMDA 3B Protein Humans YesAntagonistDetails