The interactions of putative neuroprotectant compounds with NMDA ion channels

Dale C. Sawyer
1997
The NMDA (N-methyl-D-aspartate) subtype of the receptors for the excitatory amino acid L-glutamate has been implicated as a mediator of anoxic neuronal death following periods of cerebrovascular ischaemia. Laboratory observations have implicated it in neuronal death occurring in other situations, including hypoglycemia and neurodegenerative disorders. Inhibiting the NMDA receptor could, therefore, represent a useful therapeutic intervention where CNS damage is a potential outcome resulting from
more » ... come resulting from conditions such as those given above. However, since NMDA receptors are involved in a number of vital CNS functions, such as synaptic transmission, simple all-or-none antagonism would present an unacceptable risk of toxicity and side effects. Determination of specific characteristics of a given agent's interaction with the NMDA receptor-ion channel complex would aid considerably in assessing that agent's clinical utility as a safe and efficacious neuroprotectant. The ion channel associated with the NMDA receptor is the target of a number of uncompetitive NMDA antagonists. Four such agents have been chosen for study: (-)- and (+)-β-cyclazocine are members of the benzomorphan class of compounds, several others of which are known to act as NMDA antagonists; dextromethorphan (DM) is an antitussive morphinan closely related in chemical structure to the benzomorphans; and L-687,384, which is, like a number of other uncompetitive NMDA antagonists, a ligand for sigma receptors. These agents were tested for their actions against responses to NMDA. As an estimation of the potential for producing side effects, (-)-β-cyclazocine and DM were also studied for their effects on responses to the non-NMDA glutamate receptor agonists kainate and ⍺-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazole propanoic acid (AMPA), as well as for their actions against voltage-gated Ca²⁺, Na⁺, and K⁺ currents. Finally, (-)-β-cyclazocine was tested in a cell viability assay to confirm its efficacy as a neuroprotective agent. Unitary curr [...]
doi:10.14288/1.0088342 fatcat:v5j534dbhfaxjlhh5uvcno4j6a