Allosteric modulation of ligand binding to [3H](+)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 [3H] 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 sigma 1- selective ligand [3H](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 microM phenytoin was associated with a decrease in the KD. The affinities of the sigma reference compounds caramiphen, dextromethorphan, dextrophan, (+)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 microM 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.
Department of Enzymology and Receptor Biochemistry, Collegeville, PA 19426.
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DeHaven-Hudkins
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Ford-Rice
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Allen
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Hudkins
D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D003517:Cyclopentanes / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism; D003917:Dextrorphan / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D010423:Pentazocine / Q000378:metabolism*; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
D003517:Cyclopentanes; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D003917:Dextrorphan; D014316:Tritium; D010672:Phenytoin; D003915:Dextromethorphan; C012134:SK&F 10047; C004519:caramiphen; C026539:preclamol; D010620:Phenazocine; D010423:Pentazocine