Structure-property relationships on histamine H-3-antagonists: binding of phenyl-substituted alkylthioimidazole derivatives to rat plasma proteins

The binding of a series of H-3-antagonists to rat plasma proteins was inves tigated by dialysis experiments, with RP-HPLC measurement of the free ligan d. The series was composed of 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio ]imidazoles having, on the phenyl ring, meta- and para-substituents, with d ifferent physico-chemical characteristics. As high protein binding had been proposed as being one of the features limiting brain access for the refere nce H-3-antagonist thioperamide, the title series was employed to test the possibility of achieving lower protein binding by modulation of lipophilici ty, while maintaining good receptor affinity. The compounds tested showed q uotas of bound drug ranging from 60 to 97.5%, while for thioperamide a 78% bound drug quota was observed at high total concentrations, with a steep in crease in bound percentage at lower concentrations. Two of the tested compo unds, having a carboxamide substituent, showed lower protein binding compar ed to thioperamide over a wide range of total concentration, without a sign ificant loss in affinity with respect to the parent compound. A strict depe ndence of protein binding on lipophilicity was observed, and a QSPR model w as derived which could also account for the protein binding observed for th ioperamide, while receptor affinity had been reported to be quite insensiti ve to phenyl ring substitution. It is therefore possible to modulate protei n binding of these H-3-antagonists, through lipophilicity adjustment, witho ut losing receptor affinity; this finding could help in the design of new c ompounds with improved brain access. (C) 2000 Elsevier Science S.A. All rig hts reserved.