Pharmacological specificity of several classes of drugs such as antipsychotics and antiischemic agents was assessed for σ receptors labeled with [(3)H] haloperidol. Specific binding of [(3)H] haloperidol in the presence of 25 nM spiperone was saturable and high affinity )Kd=1.96±1.31 nM, Bmax=2.37±0.27pmol/mg of protein;n=8). Among the 29 antipsychotics tested in inhibition studies, bromperidol and haloperidol were the most potent inhibitors (Ki=0.9nM, 1.0nM, respectively). The conventional antipsychotics moperone, timiperone etc. and the novel promising drugs YM-09151, Y-516, BMY-14802 and remoxipride potently inhibited [(3)H] haloperidol binding with the Ki in the range of low to moderate nanomolar. On the other hand, among the other 27 drugs tested, the antispasmodics eperisone and tolperisone, the antiischemic agents ifenprodil, the Ca(2+) antagonist flunarizine and cinnarizine, and the antitussives carbetapentane, cloperastine and dextromethorphan, were especially potent inhibitors. These results, taken together with the evidence that the antiischemic agents ifenprodil and dextromethorphan antagozine NMDA responses and NMDA receptor complex is a possible site of action for neuroprotective agents, strongly suggest that σ receptors may be potential sites of action for antiischemic as well as antipsychotic drugs, i.e., σ receptors mediate the neuroprotective effects of certain antiischemic agents by affecting the NMDA receptor complex.