Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194).
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Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P
Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194).
Mol Pharmacol. 2002 Feb;61(2):391-9.
- PubMed ID
- 11809864 [ View in PubMed]
- Abstract
Competition experiments with [(3)H]mepyramine showed that cetirizine and its enantiomers, levocetirizine and (S)-cetirizine, bound with high affinity and stereoselectivity to human H(1) histamine receptors (K(i) values of 6, 3, and 100 nM, respectively). Cetirizine and levocetirizine were 600-fold more selective for H(1) 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 H(1) 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 H(1) receptors, with half-times of 31 min and 7 min, respectively. The importance of the carboxylic function of levocetirizine for the interaction with the H(1) receptor was further supported by the results from the mutation of Lys(191) to Ala(191). 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 Thr(194) reduced the binding stereoselectivity by selectively enhancing the affinity of the distomer.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cetirizine Histamine H1 receptor Ki (nM) 3.16 N/A N/A Details Cetirizine Histamine H1 receptor Ki (nM) 79.43 N/A N/A Details Fexofenadine Histamine H1 receptor Ki (nM) 10 N/A N/A Details Hydroxyzine Histamine H1 receptor Ki (nM) 2 N/A N/A Details Hydroxyzine Histamine H1 receptor Ki (nM) 1 N/A N/A Details Terfenadine Histamine H1 receptor Ki (nM) 2 N/A N/A Details