Aurelio Orjales

Objective: We set out to establish the in vivo histamine H₁ receptor antagonistic (antihistaminic) and antiallergic properties of bilastine. Methods:In vivo antihistaminic activity experiments consisted of measurement of: inhibition of increase in capillary permeability and reduction in microvascular extravasation and bronchospasm in rats and guinea pigs induced by histamine and other inflammatory mediators; and protection against lethality induced by histamine and other inflammatory mediators in rats. In vivo antiallergic activity experiments consisted of measurement of passive and active cutaneous anaphylactic reactions as well as type III and type IV allergic reactions in sensitised rodents. Results: In the in vivo antihistaminic activity experiments, bilastine was shown to have a positive effect, similar to that of cetirizine and more potent than that of fexofenadine. The results of the in vivo antiallergic activity experiments showed that the properties of bilastine in this setting are similar to those observed for cetirizine and superior to fexofenadine in the model of passive cutaneous anaphylactic reaction. When active cutaneous anaphylactic reaction experiments were conducted, bilastine showed significant activity, less potent than that observed with cetirizine but superior to that of fexofenadine. Evaluation of the type III allergic reaction showed that of the antihistamines only bilastine was able to inhibit oedema in sensitised mice, although its effect in this respect was much less potent than that observed with dexamethasone. In terms of the type IV allergic reaction, neither bilastine, cetirizine nor fexofenadine significantly modified the effect caused by oxazolone. Conclusions: The results of our in vivo preclinical studies corroborate those obtained from previously conducted in vitro experiments of bilastine, and provide evidence that bilastine possesses antihistaminic as well as antiallergic properties, with similar potency to cetirizine and superior potency to fexofenadine.

Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants.

Objective: This study aimed to establish the receptor selectivity and antihistaminic activity of bilastine, a new selective antihistamine receptor antagonist. Design and methods:In vitro experiments were conducted using a receptor binding screening panel and guinea-pig and rat tissues. Antihistaminic activity was determined using H₁ receptor binding studies and in vitro H₁ antagonism studies conducted in guinea-pig tissues and human cell lines. Receptor selectivity was established using a receptor binding screening panel and a receptor antagonism screening conducted in guinea-pig, rat and rabbit tissues. Inhibition of inflammatory mediators was determined through the Schultz-Dale reaction in sensitised guinea-pig ileum. Results: Bilastine binds to histamine H₁-receptors as indicated by its displacement of [³H]-pyrilamine from H₁-receptors expressed in guinea-pig cerebellum and human embryonic kidney (HEK) cell lines. The studies conducted on guineapig smooth muscle demonstrated the capability of bilastine to antagonise H₁-receptors. Bilastine is selective for histamine H₁-receptors as shown in receptor-binding screening conducted to determine the binding capacity of bilastine to 30 different receptors. The specificity of its H₁-receptor antagonistic activity was also demonstrated in a series of in vitro experiments conducted on guinea-pig and rat tissues. The results of these studies confirmed the lack of significant antagonism against serotonin, bradykinin, leukotriene D₄, calcium, muscarinic M₃-receptors, α₁-adrenoceptors, β₂-adrenoceptors, and H₂- and H₃-receptors. The results of the in vitro Schultz-Dale reaction demonstrated that bilastine also has anti-inflammatory activity. Conclusions: These preclinical studies provide evidence that bilastine has H₁-antihistamine activity, with high specificity for H₁-receptors, and poor or no affinity for other receptors. Bilastine has also been shown to have anti-inflammatory properties.

In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT_1A and 5-HT_2A receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT_1A and 5-HT_2A receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and α₂ receptor. Several of these enantiomers [( − )-15b, ( − )-15j, ( − )-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K_i < 25 nM and a NET/SERT ratio K_i = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.