Binding Characteristics of Cetirizine and Levocetirizine to Human H₁Histamine Receptors: Contribution of Lys¹⁹¹and Thr¹⁹⁴

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.

In silico ligand based design of indolylpiperidinyl derivatives as novel histamine H1 receptor antagonists

“…The above interpretation is in line with mutational studies done on cetrizine, a potent H 1 receptor antagonist. Cetrizine contains a COOH group which interacts with the protonated lysine (Lys200) present in the transmembrane domain V of the H 1 receptor (30). Likewise Indolylpiperidine derivatives containing a COOH group form an ionic bond/H bond with the positively charged amino group of lysine.…”

Pharmacology of Antihistamines

“…H 1 -antihistamines, which are not structurally related to histamine, do not antagonize the binding of histamine but bind to different sites on the receptor to produce the opposite effect. For example, cetirizine cross-links sites on transmembrane domains IV and VI to stabilize the receptor in the inactive state and swing the equilibrium to the off position[13] (Figure 1C). Thus, H 1 -antihistamines are not receptor antagonists but are inverse agonists in that they produce the opposite effect on the receptor to histamine[14].…”

“…This is presumably due to "trapping" of the drug by its strong and long-lasting binding to histamine H 1 -receptors[13]. Although less active in the wheal and flare test, desloratadine has a similarly long duration of action[41].…”

Оптимізація Лікування Дітей З Інфекцією Дихальних Шляхів, Які Мають Алергічний Риніт

“…Левоцетирізин має вдвічі вищу спорідненість до H1-рецепторів порівняно з цетиризином (Gillard M. et al, 2002). При дослідженні в дітей віком 6-11 ро-ків показано, що левоцетиризин блокує 94,0 ± 0,4 % рецепторів протягом 4 годин та 60 ± 3 % рецепторів через 24 години порівняно з 90 та 57 % відповідно в дорослих (Simons K.J.…”