Binding of imipramine and cocaine to a model lipid membrane

³H]Imipramine and ³H]cocaine were concentrated at membranes of liposomes prepared from phosphatidylcholine, cholesterol, and dicetylphosphate. This binding has an apparent dissociation constant in the micromolar range and a density close to 2 pmol/g of phosphatidylcholine. The potencies of various drugs in inhibiting the binding ot liposomes correlated only weakly with those in inhibiting the high-affinity binding of ³H]imipramine and ³H]cocaine to brain membranes. However, there was a highly significant correlation between the potencies of drugs in inhibiting binding to liposomes and their lipophilic character, indicating the involvement of hydrophobic bonding. Although the amounts of phosphatidylcholine and cholesterol in brain preparations in assays for high-affinity binding to brain membranes were in the same range as those used in our assays with liposomes, the inhibition of the high-affinity binding to brain membranes was only weakly dependent upon the lipophilicity of the inhibiting drug. These results indicate that lipophilicity is but one of the factors in the complex binding interactions between lipophilic substances and integral brain membranes. In addition, the results are in agreement with the suggestion that phosphatidylcholine and cholesterol are not the primary sites of high-affinity binding ³H]imipramine and ³H]cocaine to brain membranes, although it cannot be ruled out that these lipids have different properties in natural biological membranes and in artificial liposome membranes.