Heterogenous Binding of3H‐Remoxipride to Membranes of Rat Liver and Brain

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Abstract
The binding of the antipsychotic agent3H‐remoxipride to membranes of rat liver and brain (whole brain and cerebellum) was studied with filtration technique. Saturable high affinity binding was obtained for all three types of tissue preparations. Heterogenous binding sites were found since various types of compounds inhibited the binding of3H‐remoxipride with shallow dose‐response curves. In the liver preparation it was possible to differentiate between two different binding sites. One site, called rem1, was defined with 100 nM alaproclate and bound σ2ligands with high affinity, e.g. haloperidol, GBR 12909, DTG and (+)‐3‐PPP. High correlation (r=0.93) was obtained between the inhibition of the binding of3H‐remoxipride to the rem1site and the inhibition of the binding of the σ ligand3H‐DTG reported previously (Ross 1991), indicating that the rem1site is identical to a σ2‐like binding site. The other3H‐remoxipride binding site in the rat liver, rem2, appears to be identical to the site binding alaproclate, proadifen and cocaine with high affinity. Cd2+and Zn2+were potent inhibitors of both binding sites, Cd2+particularly of rem2binding and Zn2+preferably of rem1binding. The apparent Bmax(pmol/g original tissue) and KD(nM) values for rem1binding were 441±43 and 80±14, and for rem2binding 727±116 and 95±6. The binding of3H‐remoxipride to the brain preparations was also inhibited with shallow dose‐response curves. The Bmaxvalues for the preparations of whole brain and cerebellum were 67±15 and 71±9 pmol/g original tissue, respectively and the KDvalues were 171±19 and 176±6 nM. The IC50of the compounds were highly correlated to the IC50values for the rem1binding in the liver (r=0.96) and to IC50values for the inhibition of3H‐DTG binding in rat brain reported previously (Ross 1991). Cd2+and Zn2+ions also inhibited the binding of3H‐remoxipride in the brain preparation but at higher concentrations compared with the liver preparations. The present results indicate that the main part of the binding in the brain preparations occurs to σ‐like recognition sites.