Uncompetitive inhibition of [3H]1,3-di-o-tolyl-guanidine-defined sigma binding sites by desipramine, propranolol and alprenolol in rat brain.

Desipramine, imipramine, clomipramine, (-)-propranolol, (-)-alprenolol, (+/-)-pentazocine and risperidone caused a concentration-dependent inhibition of 6 nM [3H]DTG (1,3-di-o-tolylguanidine)-defined sigma (sigma) binding with Ki values of about 0.5-2.5 microM in well-washed homogenates obtained from rat cerebral cortex. The saturation studies revealed that the inhibition by desipramine (1-4 microM), (-)-propranolol (1 microM) and (-)-alprenolol (3 microM) resulted from a reduction of the Bmax value without alteration of the Kd of [3H]DTG binding to the cortex or hippocampus. In contrast, imipramine, (+/-)-pentazocine, clomipramine and risperidone competitively attenuated the cortical or hippocampal [3H]DTG binding. These findings demonstrate the uncompetitive inhibition of [3H]DTG binding by neuroactive drugs, thereby providing further support for the possible multiple regulation of cerebral sigma receptors.