Abstract—Depressant drugs are considered to exert their pharmacological effects as a result of membrane interactions determined by their physico‐chemical properties. In this study, a correlation was found between lipid solubility and potency of various local anaesthetics, antihistamines, tricyclic antidepressants and phenothiazine tranquilizers as inhibitors of the Na, K‐ATPase activity of a microsomal membrane fraction from bovine brain cortex. Depressant drugs such as chlorpromazine, which have the greatest lipid solubilities, were competitive inhibitors of Na activation but noncompetitive toward K activation, whereas drugs such as tetracaine with lower lipid solubilities were competitive inhibitors of K activation but noncompetitive toward Na activation. Drugs with intermediate lipid solubilities were mixed competitive‐noncompetitive inhibitors of both Na and K activation. Both chlorpromazine and tetracaine competitively inhibited cation activation by a heterotropic allosteric mechanism, probably mediated through membrane conformational changes. Whereas quaternization or a decrease in the incubation pH interfered with the ability of chlorpromazine to inhibit Na activation in a competitive fashion, these changes did not affect the ability of tetracaine to compete with K activation. In addition Mn, Ca and phosphatidyl serine were very effective non‐competitive antagonists of chlorpromazine inhibition of Na, K‐ATPase, whereas these agents competitively antagonized tetracaine inhibition to a lesser extent. These data suggest that the more lipid soluble phenothiazines penetrate into and react in hydrophobic areas of the membrane microenvironment, resulting in a membrane perturbation which interferes with Na activation. On the other hand the less lipid soluble local anaesthetics probably act at superficial sites near the membrane surface, resulting in a different membrane perturbation which interferes with the K activation mechanism. It is suggested that lipid solubility may be a significant factor in determining selectivity in the membrane interactions of various pharmacological agents and hence differences in pharmacological activity among different classes of depre