The tyrocidine antibiotic polypeptides are known to exhibit self-association. They were therefore used as test substances to document the behavior to be expected by the method of thin-film dialysis. Self-association with these peptides is indicated by concentration dependence, a reverse curvature of the escape plot, and a retardation of the rate of diffusion by addition of salt but an acceleration by the addition of ethanol or other hydrophobic bond breaking solvent additives. A survey of dipeptides by thin-film dialysis has revealed that L-lysyl-L-lysine, L-lysyl-L-arginine, and L-histidyl-L-histidine exhibit a behavior characteristic of self-association in a pH region where all the acidic and basic T A he so-called quaternary structures of proteins and nucleotides are thought to result from the interplay of various binding forces such as hydrophobic bonds, coulombic forces, 7r bonds, and hydrogen bonds. The contribution of each individual interaction or small section of the molecule is considered to be relatively weak as compared with most covalent bonds but their sum in concerted effect can be strong. Such a theory agrees well with experience but leaves much to be understood about the detailed nature of each type of interaction and its contribution to the whole. A truly clear understanding is made uncertain by the many variables
Although the capacity of the animal organism for causing transformations of drugs has been recognized, many studies of the pharmacological or therapeutic activities of various substances appear in which this factor has not been taken into consideration. Thus frequently, the observed effect has been related to the dosage of a given drug or to drug levels in various parts of the body as determined spectrophotometrically. By the latter method, confusion may occur between the identification of the drug administered and metabolic products of the drug which, while actually being the active agent or agents, still sholy spectrographic properties closely similar to the drug itself. Often this has been the only feasible approach because of the difficulty in the detection, isolation and identification of the small amounts of the transformation products carried in the complicated mixture present in the biological fluids. The need for such information, often realized in the past, is obvious for the proper evaluation or interpretation of the underlying cause of the desired effect.The method of counter-current distribution (1) is an approach which should prove helpful for the problem as stated, because of the quantitative nature of the process and other advantages mentioned in previous publications (2). An excellent opportunity to test this thesis came with the appraisal of the 4-aminoquinoline group of drugs as among the most effective suppressive antimalarials, and the need for knowledge of the fate and physiological disposition of representative members of the series. It was thought that information on the mechanism of detoxification of the drugs could prove of value both as a guide to more efficient administration of the substances and as a source of leads for the synthesis of perhaps even more highly useful drugs.In the present investigation, the metabolic fate of three typical 4-aminoquinolines as indicated by the nature of the degradation products isolated from the urine of normal human volunteers receiving the drugs has been the subject of a preliminary study. Unfortunately, termination of hostilities prevented accumulation of sufficient material to enable the studies to be carried as far as might have been desired. The drugs investigated were 4-(4-diethylamino-1-methylbutylamino)-7-chloroquinoline (chloroquine) (SN-7618) (I),2 4-(3-di-
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