Comparative study of central and peripheral histamine‐H1 receptor binding in vitro and ex vivo of non‐sedating antihistamines and of noberastine, a new agent

A new antihistamine, noberastine, and clinically used non‐sedating antihistamines, astemizole, mequitazine, terfenadine, loratadine, and cetirizine were investigated for in vitro and ex vivo binding to histamine‐H1 receptors in guinea‐pig cerebellums and lungs. In vitro, all the drugs dissociated slowly from histamine‐H1 receptors (half‐times ≥ 100 min), Ki,app‐values decreased with longer incubation times and for potent lipophilic agents (astemizole, mequitazine, and terfenadine) Ki,app‐values were lower with more dilute tissue suspensions. Because of the slow dissociation, true binding equilibrium cannot be attained during limited incubation times and because of the apparently high tissue adsorption for some of the drugs, the actual free drug concentration in solution is unknown. Therefore measured binding parameters are apparent; true equilibrium binding constants cannot be estimated. Noberastine showed the lowest Ki,app‐value in various assay conditions (0.55–0.15 nM). In optimized assay conditions astemizole and mequitazine were nearly as potent (Ki,app‐values 0.2 and 0.29 nM). Terfenadine, cetirizine, and loratidine bound with 30‐, 80‐ and 100‐times lower affinity. The in vitro receptor binding and neurotransmitter inhibition profile of these compounds revealed that they all primarily bound to histamine‐H1 receptors. The occupation of lung and cerebellar histamine‐H1 receptors was investigated after oral administration of different dosages of the drugs and at various times after drug administration using ex vivo binding techniques. Noberastine and astemizole were the most potent componds and showed complete differentiation between lung and cerebellar receptor occupation (with 0.63 mg.kg−1: 70% lung receptor occupancy, less than 10% cerebellar receptor occupancy). With mequitazine and terfenadine a 7‐times higher dose was required to reach the same effect. Astemizole was extremely long acting, noberastine, mequitazine and terfenadine were short acting. Loratidine and cetirizine differentiated very poorly or not at all between lung and cerebellar receptor occupation (at 2.5 mg.kg−1: 70% and 60% lung receptor occupation, 50% and 70% cerebellar receptor occupation). The physicochemical properties of the drugs were considered in the discussion of the data. It appeared that penetration into the brain is not directly related to lipophilicity. The study allowed a quantitative comparison of the receptor binding properties of the drugs. Noberastine, as a shorter acting agent, and astemizole, as a long acting agent, appeared to be the compounds of choice as non‐sedating antihistamines.