ALLOSTERIC MODULATION OF PERIPHERAL SIGMA-BINDING SITES BY A NEW SELECTIVE LIGAND - SR-31747

The interactions of a new compound SR 31747 with sigma sites were exam ined 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 [H -3](+)-pentazocine, [H-3](+)-3PPP and [H-3]DTG on rat spleen membranes . Characterization of SR 31747 binding sites using [3H]SR 31747 as a l igand showed that this compound binds reversibly, with high affinity t o one class of sites on rat spleen membranes (K-d 0.66 nM, B-max 5646 fmol/mg protein). The pharmacological profile of [H-3]SR 31747 binding sites was consistent with the presence of specific sites distinct fro m classical sigma 1 and sigma 2 receptor subtypes strongly suggesting an allosteric modulation of sigma sites by SR 31747. Similarly, [H-3]S R 31747 binding sites were demonstrated on human PBL and also on purif ied 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 [ H-3](+)-3PPP to mice spleen membranes with ED(50) 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 throug h allosteric modulation of peripheral sigma sites.