Computer-assisted comparison of the structural and electronic dispositions of ebastine and terfenadine

Ebastine and terfenadine are both marketed nonsedating H1 histamine receptor antagonists. Although apparently similar in chemical structure, the compounds have different pharmacological profiles, particularly with respect to cardiac effects. These effects are consistently observed in a wide range of experimental models with terfenadine, but not with ebastine, despite the fact that the latter is more potent as an antihistamine. The objective of this study was to provide a structural basis to explain such differences.

A complete computer-assisted conformational and electronic characterisation was made for both drugs.

The preferred 3-dimensional spatial orientations were found to be different, as were the molecular locations of the highest occupied and lowest unoccupied molecular orbitals. Furthermore, for terfenadine, additional points of interaction as a hydrogen bond donor were found, which were not evident in ebastine or other noncardiotoxic antihistamines. These extra points of interaction were also found in other compounds that have shown cardiac effects similar to those of terfenadine.