title: Differences in the allosteric modulation by phenytoin of the binding properties of the sigma1 ligands [3H](+)-pentazocine and [3H]NE-100.
abstract: The present study evaluated the effects of phenytoin (DPH) on the binding to synaptosomal fraction membranes from guinea pig brain of the prototypic sigma1 (sigma1) receptor agonist [3H](+)-pentazocine and the putative sigma1 antagonist [3H]NE-100. Equilibrium and binding kinetics studies were done. The order of affinity of 12 sigma1 ligands for binding sites labeled with [3H](+)-pentazocine correlated well with their order of affinity for sites labeled with [3H]NE-100, suggesting that both radioligands label the same receptor. Phenytoin increased the binding of [3H](+)-pentazocine, enhancing its affinity (K(D) value) for sigma1 receptors and decreasing its dissociation rate from these receptors. The maximal number of receptors (B(max) value) labeled with [3H](+)-pentazocine was not changed. In contrast, phenytoin decreased the specific binding and maximal number of receptors labeled with [3H]NE-100, and increased its dissociation rate from sigma1 receptors. The affinity of this radioligand for sigma1 receptors was not modified. In conclusion, phenytoin behaved as a positive allosteric modulator on the binding of [3H](+)-pentazocine, whereas it negatively modulated the binding of [3H]NE-100. These results add evidence in favor of the use of phenytoin in vitro to distinguish between agonists and antagonists of sigma1 receptors.
authors.affiliation: Department of Pharmacology and Institute of Neuroscience, School of Medicine,University of Granada, 18012 Granada, Spain.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Cobos
authors.forename: Gema
authors.initials: G
authors.lastname: Lucena
authors.forename: José M
authors.initials: JM
authors.lastname: Baeyens
authors.forename: Esperanza
authors.initials: E
authors.lastname: Del Pozo
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003627:Data Interpretation, Statistical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D010423:Pentazocine / Q000378:metabolism*; D010672:Phenytoin / Q000378:metabolism* / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D000840:Anisoles; D000927:Anticonvulsants; D011437:Propylamines; D017465:Receptors, Opioid, delta; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D010672:Phenytoin; D010423:Pentazocine