ALLOSTERIC MODULATION OF LIGAND-BINDING TO [H-3] (+)PENTAZOCINE-DEFINED SIGMA-RECOGNITION SITES BY PHENYTOIN

The allosteric modulation of sigma recognition sites by phenytoin (diphenylhydantoin) has been demonstrated by the ability of phenytoin to stimulate binding of various [H-3]sigma ligands, as well as to slow dissociation from sigma sites and to shift sigma sites from a low- to a high-affinity state. Phenytoin stimulated the binding of the sigma1-selective ligand [H-3](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 muM phenytoin was associated with a decrease in the K(D). The affinities of the sigma 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 muM phenytoin. The relative sensitivity of sigma compounds to allosteric modulation by phenytoin is not a property of all sigma ligands, and may provide an in vitro basis for distinguishing actions of sigma compounds and predicting sigma effects in vivo.