Melatonin (MLT) is known for its radical scavenger activity, which had been related to its ability to protect neuronal cells from different kinds of oxidative stress. In particular, MLT protects rat cerebellum granular cells from kainate-induced necrosis at concentrations higher than 100 microM, and is able to reduce lipoperoxidation induced by radical stress in rat brain homogenate at similar concentrations. On the other hand, MLT has nanomolar affinity for its membrane receptors (MT1 and MT2), and these are completely saturated at the high concentrations employed when the cytoprotective effect is observed. Other indole derivatives are also known to possess antioxidant and cytoprotective activity. In order to dissociate the cytoprotective effect of MLT from its receptor affinity, and to investigate the structure-activity relationships (SAR) between this effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of MLT was gradually modulated, varying the 5-methoxy group nature and position, the acylaminoethyl chain position, and by the introduction of lipophilic groups. These modifications resulted in a set of compounds having different receptor affinity and intrinsic activity, different lipophilicity, and different substitution at the indole nucleus. The compounds were tested for their antioxidant potency by the ABTS test and by inhibition of rat brain homogenate lipoperoxidation; their cytoprotective effect was also estimated from the inhibition of kainate-induced cellular death on rat cerebellum granular cells, and the results were evaluated by SAR comparison and QSAR analysis. An isomer of MLT resulted more potent and effective than MLT itself in the cytoprotection test, although it showed similar potency in the peroxidation test, and it was devoid of the ability to stimulate MT1 and MT2 receptors. This compound was selected as the lead compound for a further SAR study, devoted to the optimization of the cytoprotective effect and to the investigation on its mechanism.