Abstract <p>NMDA (N-methyl-D-aspartate) receptors are inhibited by manyguanidine-containing compounds at micromolar and submicromolar concentrations. Amongthe natural guanidine-containing inhibitors of NMDA receptors isthe arginine metabolite agmatine, while synthetic ones include thepancreatitis drug nafamostat, the antidiabetic drug phenformin,and the antimalarial compounds proguanil and cycloguanil. In thiswork, we for the first time tested two other guanidine-containingdrugs for activity against NMDA receptors—brimonidine, used to treatglaucoma and ocular hypertension, and cimetidine, used to treatpeptic ulcer disease. Experiments were carried out on isolated pyramidalneurons from the hippocampal CA1 region of Wistar rats. Cells wereisolated from slices by vibrodissociation; currents were recordedusing the whole-cell patch-clamp technique. Brimonidine and cimetidineinhibited NMDA receptors with an IC₅₀ of about100 µM. Their action was non-competitive and voltage-dependent,suggesting NMDA receptor channel pore blockade as the primary molecular mechanismof their action on these receptors. The relatively weak activityof brimonidine and cimetidine suggests that the inhibition of NMDAreceptors does not contribute significantly to their therapeutic actionor side effects. Presumably, this weak activity is due to the absenceof sufficiently bulky hydrophobic groups in the structure of cimetidineand brimonidine, which distinguishes them from highly active amidine-or guanidine-containing NMDA receptor blockers, such as nafamostat,pentamidine, and furamidine.</p>