Chiral manipulation of drug selectivity: Studies on a series of terfenadine-derived dual antagonists on H₁-receptors and calcium channels

Abstract

A series of terfenadine derivatives were evaluated for enantioselectivity on histamine H₁-receptors and calcium channels. Whereas H₁-receptors are only sterically discriminative against the benzhydryl part of the molecules, calcium channels showed enantioselectivity to either the phenylbutyl part or the benzhydryl part provided that an appropriate lipophilicity is preserved at the chiral site. It is speculated that the hydrophilicity of the butanol moiety is responsible for the lack of stereoselectivity of terfenadine enantiomers since it drives the side chain out the stereoselective site of calcium channels, which are lipophilic. In four different test systems, (guinea-pig ileum, guinea-pig lung membranes, rat aorta and rat cortex mebranes), this series of compounds generally showed about 10 times higher activity on H₁-receptors than on calcium channels. By introducing a chiral center in the different parts of the molecule we were able to increase the selectivity of an enantiomer VUF4648 to calcium channels.