Ca(2+)-activated non-selective cation (CAN) channels are activated by cytoplasmic Ca(2+) and I(CAN) underlies many slow depolarizing processes in neurons including a putative role in excitotoxicity. CAN channels in many non-neuronal cells are blocked by non-steroidal antiinflammatory drugs that are derivatives of diphenylamine-2-carboxylate (DPC). The DPC derivative flufenamate (FFA) has a complex effect on certain neurons, whereby it blocks CAN channels and increases [Ca(2+)](i). We report here that FFA, but not the parent compound, DPC, blocks CAN channels in hippocampal CA1 neurons. As was the case in other neurons, the effects of FFA are complex and include a maintained rise in [Ca(2+)](i). Furthermore, the CAN channel blocking ability of FFA persists even when the channels have been potentiated by a Ca(2+)-dependent process. The use of a CAN channel-blocking drug is important for delineating CAN channel-dependent processes and may provide a basis for therapy for CAN channel-dependent events in ischemia.