STEREOSELECTIVE DIFFERENCES IN THE BINDING OF N-METHYLATED BARBITURATES TO HUMAN SERUM-ALBUMIN

The binding to human serum albumin (HSA) of a homologous series of N-m ethylated chiral barbiturates was studied by means of equilibrium dial ysis. The length of the aliphatic side chain at C-5 of the barbiturate ring was variable, and the compounds used were: (+)-(S)-and (-)-(R)-5 -methyl-(A), -5-ethyl-(B), -5-propyl- (C) and -5-butyl-(D)-1-methyl-5- phenyl-barbiturate. Binding parameters (numbers of binding classes and of binding sites in each class, affinity constant, total binding cons tant) were obtained from the Scatchard plot of the percent binding val ues. For both enantiomers of A and D as well as for (-)-(R)-B 2 classe s were obtained; (+)-(S)-B and both enantiomers of C had only 1 class. The total binding constant (K) indicated a more than twofold higher b inding of (-)-(R)-B (2.64 x 10(3) . mol(-1)) and C (5.75 x 10(3). mol( -1)) compared with the corresponding (+)-(S)-enantiomer (1.02 and 2.00 x 10(3) . mol(-1), respectively); in the case of D the (+)-(S)-enanti omer was preferentially bound (K = 10.14 vs. 5.40 x 10(3) . mol(-1) fo r the (-)-(R)-enantiomer). The percent binding values of (+)-(S)-A wer e higher than those of (-)-(R)-A; however, the K-values of the A-enant iomers were almost identical.