CHIRAL MANIPULATION OF DRUG SELECTIVITY - STUDIES ON A SERIES OF TERFENADINE-DERIVED DUAL ANTAGONISTS ON H-1-RECEPTORS AND CALCIUM CHANNELS

A series of terfenadine derivatives were evaluated for enantioselectiv ity on histamine H-1-receptors and calcium channels. Whereas H-1-recep tors are only sterically discriminative against the benzhydryl part of the molecules, calcium channels showed enantioselectivity to either t he phenylbutyl part or the benzhydryl part provided that an appropriat e 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 si de chain out of the stereoselective site of calcium channels, which ar e lipophilic. In four different test systems, (guinea-pig ileum, guine a-pig lung membranes, rat aorta and rat cortex membranes), this series of compounds generally showed about 10 times higher activity on H-1-r eceptors than on calcium channels. By introducing a chiral center in t he different parts of the molecule we were able to increase the select ivity of an enantiomer VUF4648 to calcium channels.