Allosteric modulation of ligand binding to [ 3H](+)pentazocine-defined σ recognition sites by phenytoin

The allosteric modulation of σ recognition sites by phenytoin (diphenylhydantoin) has been demonstrated by the ability of phenytoin to stimulate binding of various [ 3H]σ ligands, as well as to slow dissociation from σ sites and to shift σ sites from a low- to a high-affinity state. Phenytoin stimulated the binding of the σ 1-selective ligand [ 3H](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 μM phenytoin was associated with a decrease in the K D. The affinities of the σ reference compounds caramiphen, dextromethorphan, dextrorphan, (+)3-PPP and (+)SKF-10.047 were three- to eight-fold higher, while the affinities of benzetimide, BMY-14802, carbetapentane, DTG and haloperidol were unchanged in the presence of 250 μM phenytoin. The relative sensitivity of σ compounds to allosteric modulation by phenytoin is not a property of all σ ligands, and may provide an in vitro basis for distinguishing actions of σ compounds and predicting σ effects in vivo.