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.
DeHaven-Hudkins
D L
DL
Department of Enzymology and Receptor Biochemistry, Collegeville, PA 19426.
Ford-Rice
F Y
FY
Allen
J T
JT
Hudkins
R L
RL
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