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.

ABSTRACT:The objective of this study was to compare the blood-brain barrier (BBB) transport and brain distribution of levo-(R-CZE) and dextrocetirizine (S-CZE). Microdialysis probes, calibrated using retrodialysis by drug, were placed into the frontal cortex and right jugular vein of eight guinea pigs. Racemic CZE (2.7 mg/kg) was administered as a 60-min i.v. infusion. Unbound and total concentrations of the enantiomers were measured in blood and brain with liquid chromatography-tandem mass spectrometry. The brain distribution of the CZE enantiomers were compared using the parameters K p, K p,u, K p,uu , and V u,br . K p compares total brain concentration to total plasma concentration, K p,u compensates for binding in plasma, whereas K p,uu also compensates for binding within the brain tissue and directly quantifies the transport across the BBB. V u,br describes binding within the brain. The stereoselective brain distribution indicated by the K p of 0.22 and 0.04 for S-and R-CZE, respectively, was caused by different binding to plasma proteins. The transport of the CZE enantiomers across the BBB was not stereoselective, since the K p,uu was 0.17 and 0.14 (N.S.) for S-and R-CZE, respectively. The K p,uu values show that the enantiomers are effluxed to a large extent across the BBB. The V u,br of approximately 2.5 ml/g brain was also similar for both the enantiomers, and the value indicates high binding to brain tissue. Thus, when determining stereoselectivity in brain distribution, it is important to study all factors governing this distribution, binding in blood and brain, and the BBB equilibrium.

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SUMMARY This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, hi addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate tbe release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic a-adrenoceptors reduces this release of transmitter and tbe reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic aradrenoceptors that mediate the responses of certain organs and the presynaptic aradrenoceptors that modulate the NE release during nerve stimulation. Therefore, subdassification of a-adrenoceptors into a, and a, subtypes is warranted but must be considered to be independent of the anatomical location of these receptors.Some noradrenergic nerve endings have also been shown to possess /3-adrenergic receptors, tbe stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinepbrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the Inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransraission and the subdassification of a-adrenoceptors to tbe treatment of hypertension is presented. Gonidtne, for example, appears to be a potent aradrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an a,-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic aradrenoceptors, which might contribute to its cardiovascular action.The antihypertensive effects of a-methyldopa are related to tbe formation of a-methylnorepinephrine, a preferential a r adrenoceptor agonist, which can stimulate peripheral presynaptic aradrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone.