An N-methyl-D-aspartate receptor channel blocker with neuroprotective activity

Excitotoxicity, resulting from sustained activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype, is considered to play a causati ve role in the etiology of ischemic stroke and several neurodegenerative di seases. The NMDA receptor is therefore a target for the development of neur oprotective agents. Here, we identify an N-benzylated triamine (denoted as NBTA) as a highly selective and potent NMDA-receptor channel blocker select ed by screening a reduced dipeptidomimetic synthetic combinatorial library. NBTA blocks recombinant NMDA receptors expressed in Xenopus laevis oocytes with a mean IC50 of 80 nM; in contrast, it does not block GluR1, a glutama te receptor of the non-NMDA subtype. The blocking activity of NBTA on NMDA receptors exhibits the characteristics of an open-channel blocker: (i) no c ompetition with agonists, (ii) voltage dependence, and (iii) use dependence . Significantly, NBTA protects rodent hippocampal neurons from NMDA recepto r, but not kainate receptor-mediated excitotoxic cell death, in agreement w ith its selective action on the corresponding recombinant receptors. Mutage nesis data indicate that the N site, a key asparagine on the M2 transmembra ne segment of the NR1 subunit, is the main determinant of the blocker actio n. The results highlight the potential of this compound as a neuroprotectan t.