Inhibitory effect of phenothiazines on the binding of [3H]perazine to alpha 1-acid glycoprotein.

A system is described which allows the determination of the affinity constant of unlabelled drugs to alpha 1-acid glycoprotein (alpha 1-AGP) by displacing [3H]perazine from the binding protein with equilibrium dialysis. All drugs investigated appear to bind to only one site at the alpha 1-AGP molecule. From experiments, in which the chemical structure of the displacers was varied, the fragment 21-31 of the amino acid sequence appears to be a candidate for hydrophobic interactions. The glutamic acids 177 and 178 of the alpha 1-AGP molecule could be involved in ionic interactions with the side chain of phenothiazine derivatives. The relevance of alpha 1-AGP for drug binding, distribution, and the possible reasons for insufficient correlation between psychotropic plasma concentration and therapeutic response is discussed.