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

Bioorg Med Chem. 2007 Feb 1;15(3):1525-32. doi: 10.1016/j.bmc.2006.09.060. Epub 2006 Sep 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Animals
  • Brain / drug effects
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Ion Channels
  • Male
  • Mice
  • Mice, Inbred ICR
  • Models, Molecular
  • Phencyclidine / analogs & derivatives
  • Piperidines / pharmacology
  • Radioligand Assay
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Synaptosomes / drug effects*
  • Thiophenes / pharmacology

Substances

  • Amines
  • Excitatory Amino Acid Antagonists
  • Ion Channels
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Thiophenes
  • Dizocilpine Maleate
  • tenocyclidine
  • Phencyclidine