SAR studies of butamidine derivatives with the NMDA receptor complex revealed that hydrophobic rather than hydrophilic linkers between the amidinophenyl groups promote NMDA antagonism. Conformation of the linker did not influence binding in the absence of bis-methoxy substituents ortho to the linker. Like pentamidine, the compounds are noncompetitive NMDA receptor antagonists. 0 1997 Elsevier Science ~rd.