Abstract

This study evaluated the interaction of the arcaine analog 1,10-bis(guanidino)decane (BG10) with the NMDA receptor. BG10 inhibited [3H]dizocilpine binding to well-washed rat brain membranes with an apparent affinity of 1.3 microM. The inhibition was not competitive with respect to glutamate or glycine, but was significantly altered by spermidine. However, unlike arcaine, BG10 slowed the dissociation of [3H]dizocilpine. BG10 also inhibited [3H]glycine binding at similar concentrations. BG10 inhibited N-methyl-D-aspartate (NMDA) and glycine-induced increases in intracellular Ca++ in cultured rat brain neurons monitored using the fluorescent dye, fura-2 (IC50 3 microM). This inhibition was not competitive with NMDA or glycine and could not be reversed by either spermidine or arcaine. BG10 also noncompetitively inhibited NMDA-stimulated cyclic GMP production in cerebellar slices from mouse brain. Finally, BG10 administered i.p. reduced harmaline-stimulated, NMDA-dependent cyclic GMP accumulation in mouse cerebellum in vivo (ED50 12.3 mg/kg). These data demonstrate that BG10 is a novel and effective NMDA receptor antagonist in vitro and in vivo.