Serotonin uptake inhibitors differentially modulate high affinity imipramine dissociation in human platelet membranes

The influence of selective serotonin uptake inhibitors on the dissociation rate of 3H-imipramine from its high affinity binding site in human platelet membranes was studied. Of the uptake inhibitors tested, one group of compounds attenuated dissociation, another group accelerated it, while a third group had little effect on the dissociation process. Drugs unrelated to the serotonin uptake system were ineffective. Removal of sodium ions markedly increased imipramine dissociation. Dose response curves of the active compounds indicated that micromolar concentrations were required to exert an effect on imipramine dissociation. These results can be adequately explained by an allosteric model which includes effector binding sites and distinct conformational states of the high affinity imipramine binding site.