Optically active analogues of ebastine: synthesis and effect of chirality on their antihistaminic and antimuscarinic activity.
A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4-methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described.
Zhang
M Q
MQ
Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, The Netherlands.
Walczynski
K
K
Ter Laak
A M
AM
Timmerman
H
H
D000818:Animals; D002090:Butyrophenones / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000138:chemical synthesis* / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D013237:Stereoisomerism
D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D018727:Muscarinic Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D006632:Histamine; C058249:ebastine