Structure-activity relationship (SAR) studies of N,N'-diarylguanidines as glutamate release inhibitors led to the synthesis of N-(acenaphth-5-yl)-N'-(4-methoxynaphth-l-yl)guanidine (6). Compound 6, with IC50 values of 1.3 and 2.2 I.tM in 14C-guanidine flux and 45Ca 2+- flux assays respectively, effectively inhibited both veratridine and K+-evoked glutamate release in rat brain synaptosomal preparations.There is a great deal of interest in developing drug treatments which limit the extent of nerve cell death following an ischemic insult to the brain. Nerve cell death following ischemia is thought to result from the actions of excessive glutamate released from metabolically compromised nerve terminals. 1-3 Glutamate binds to both N-methyl-D-aspartate (NMDA) and non-NMDA receptor sites to elicit its neurotoxic effects. NMDA antagonists are highly effective in animal models of focal cerebral ischemia, 4 but are reportedly less effective in models of global cerebral ischemia. 5,6 Non-NMDA antagonists such as NBQX are highly effective in rat models of global cerebral ischemia, 7 but are apparently less effective in focal cerebral ischemia. 8 However, blockers of glutamate release prevent excessive activation of both NMDA and non-NMDA receptor subclasses by acting at an earlier stage of the cascade of events leading to cell death. Although the release of neurotransmitters other than glutamate may also be affected, glutamate release blockers have recently been shown to be effective in animal models of both focal and global cerebral ischemia.9,10 Presynaptic voltage-activated Ca 2+ channels and Na + channels each play an important role in regulating the release of glutamate from presynaptic nerve terminals, and specific subtypes of these channels may play differential roles in the release of particular transmitters. 11 Accordingly, blockade of the voltage-activated ion channels which control glutamate release is considered as an approach toward developing potential neuroprotective agents.