title: Allosteric modulation of peripheral sigma binding sites by a new selective ligand: SR 31747.
abstract: The interactions of a new compound SR 31747 with sigma sites were examined in rat spleen membranes and in human peripheral blood leukocytes (PBL). Nanomolar concentrations of SR 31747 selectively inhibited in a non-competitive manner the binding of the prototypic sigma ligands [3H](+)-pentazocine, [3H](+)-3PPP and [3H]DTG on rat spleen membranes. Characterization of SR 31747 binding sites using [3H]SR 31747 as a ligand showed that this compound binds reversibly, with high affinity to one class of sites on rat spleen membranes (Kd 0.66 nM, Bmax 5646 fmol/mg protein). The pharmacological profile of [3H]SR 31747 binding sites was consistent with the presence of specific sites distinct from classical sigma 1 and sigma 2 receptor subtypes strongly suggesting an allosteric modulation of sigma sites by SR 31747. Similarly, [3H]SR 31747 binding sites were demonstrated on human PBL and also on purified subpopulations of human mononuclear cells (granulocytes, NK cells, T4, T8 and B lymphocytes). Administered to mice by i.p. or oral route 30 min before sacrifice, SR 31747 strongly inhibited the binding of [3H](+)-3PPP to mice spleen membranes with ED50 values of 0.18 and 1.43 mg/kg, respectively. Taken together these results could suggest a potential immunological activity of SR 31747 either directly or through allosteric modulation of peripheral sigma sites.
authors.affiliation: Sanofi Recherche, Montpellier, France.
authors.forename: R
authors.initials: R
authors.lastname: Paul
authors.forename: S
authors.initials: S
authors.lastname: Lavastre
authors.forename: D
authors.initials: D
authors.lastname: Floutard
authors.forename: R
authors.initials: R
authors.lastname: Floutard
authors.forename: X
authors.initials: X
authors.lastname: Canat
authors.forename: P
authors.initials: P
authors.lastname: Casellas
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
authors.forename: J C
authors.initials: JC
authors.lastname: Brelière
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003510:Cyclohexanes / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D003510:Cyclohexanes; D008024:Ligands; D017480:Receptors, sigma; C088447:SR 31747