Sigma receptors are present in many organs and several functions are allotted to them but the specificity of their effect remains to be established. Indeed, all the molecules known to interact with these receptors also have affinities for other receptors. Recently, sigma-1 receptors were implied in the processes of cellular protection, several of their ligands showing a neuroprotector effect in various models of cerebral ischaemia. S-16950, a trimetazidine derivative, is a powerful anti-ischaemic drug on a hepatic model of ischaemia-reperfusion. It is structurally closely related to SA4503, a sigma receptor ligand showing also an anti-ischaemic action. Our study shows that S-16950 inhibits the binding of [3H]pentazocine, a selective sigma-1 receptor radioligand, to rat brain membranes with a high affinity (IC50 = 7 nM). This affinity is equivalent to the most potent sigma ligand such as haloperidol. Its affinity is 170 times higher for the sigma-1 subtype than for the sigma-2 subtype. The effect of Gpp[NH]p on S-16950 inhibition of [3H]pentazocine binding and the potentiation of the convulsivant effect of cocaine under the action of S-16950 suggest that this molecule may act as an agonist. These results indicate that S-16950 is a new sigma ligand and reinforce the assumption of a link between sigma receptors and a cytoprotective activity.

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