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Vol. 61, Issue 2, 391-399, February 2002

Binding Characteristics of Cetirizine and Levocetirizine to Human H1 Histamine Receptors: Contribution of Lys191 and Thr194

Michel Gillard, Christy Van Der Perren, Nicole Moguilevsky, Roy Massingham, and Pierre Chatelain

UCB S.A. Pharma Sector, In Vitro Pharmacology, Braine l'Alleud, Belgium (M.G., C.V.D.P., R.M., P.C.); and Laboratory of Applied Genetics, Institute of Molecular Biology and Medicine, Free University of Brussels, Gosselies, Belgium (N.M.)

Competition experiments with [3H]mepyramine showed that cetirizine and its enantiomers, levocetirizine and (S)-cetirizine, bound with high affinity and stereoselectivity to human H1 histamine receptors (Ki values of 6, 3, and 100 nM, respectively). Cetirizine and levocetirizine were 600-fold more selective for H1 receptors compared with a panel of receptors and channels. Binding results indicated that the interaction between cetirizine, its enantiomers, and histamine is compatible with a competitive behavior, in contrast with the noncompetitive profile of cetirizine and levocetirizine observed in isolated organs. Binding kinetics provided a suitable explanation for this observation, because levocetirizine dissociated from H1 receptors with a half-time of 142 min; that of (S)-cetirizine was only 6 min, implying that the former could act as a pseudo-irreversible antagonist in functional studies. The carboxylic function of levocetirizine seemed responsible for its long dissociation time. Indeed, hydroxyl or methyl ester analogs dissociated more rapidly from H1 receptors, with half-times of 31 min and 7 min, respectively. The importance of the carboxylic function of levocetirizine for the interaction with the H1 receptor was further supported by the results from the mutation of Lys191 to Ala191. This mutation decreased the dissociation half-time of levocetirizine from 142 to 13 min and reduced its affinity from 3 to 12 nM, whereas the affinity and dissociation kinetics of hydroxyl and methyl ester analogs were hardly affected. The mutation of Thr194 reduced the binding stereoselectivity by selectively enhancing the affinity of the distomer.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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