Uncompetitive N-Methyl-D-aspartic acid receptor (NMDAR) antagonism is an important pharmacological strategy in the therpay for various neurodegenerative diseases including Alzheimer's disease and other dementias.  Using a phencyclidine pharmacophore, a series of novel conformationally restricted arylbicycloheptylamines have been designed and synthesized as novel uncompetitive NMDAR antagonists.  Several of the compounds exhibited moderate to significant binding affinity (Ki) for the PCP site of the NMDAR channel as measured by in vitro competition studies using 3H-MK-801 in rat forebrain.  Several compounds have shown selectivity for NMDAR over other CNS sites as compared to their non-constrained analogs.  Binding values at additional CNS receptor sites, measured by in vitro studies are presented.  In vitro neuroprotection studies using NMDA induced toxicity in rat Hippocampal slices are presented.  Finally, several compounds displayed promising in vivo neuroprotection in the maximal electroshock test in rat and mice.

Arylbicycloheptylamines as novel uncompetitive NMDA receptor antagonists

244th National Meeting (2012)

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