Molecular Pharmacology, Vol 12, 612-619, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

The Role of Substituents in the Hydrophobic Binding of the 1,4-Benzodiazepines by Human Plasma Proteins

¹ Division of Experimental Therapeutics, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110

The effect on the extent of plasma protein binding by varying the substituents on the basic benzodiazepine molecule has been studied. Hansch lipophilic substituent constants were calculated for each substituent on the molecule. A correlation was found between the degree of protein binding and changes in the lipophilic nature of the molecule as measured by the summation of its lipophilic substituent constants. Protein binding increased with the increasing lipophilic character of substituents in positions 1,2,3,4,7, and 4'. The electronic character of substituents in position 1, 3, or 7, as expressed by their Hammett constant (), was also found to correlate with the observed protein binding. Changes in protein binding with respect to various 2'-substituents were not related to the lipophilic nature of the 2'-substituents but may be the result of changes in the spatial orientations of the benzodiazepine molecule in relation to its albumin binding loci. It was concluded that the major factor in determining the extent of 1,4-benzodiazepine binding to human plasma proteins is the degree of lipophilicity of the molecule. Substituents which affect the conformation of the molecule, such as those in position 2', also affect the extent of binding.

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ACKNOWLEDGMENTS The authors thank Dr. George C. S. Yu of the Department of Research Statistics for his valuable contributions to the statistical analysis of the data presented.