Section II: Antihistamines
Fexofenadine Highly Selective for H1 Receptor
John Ellis, PhD, Pennsylvania State University School of Medicine,
Hershey, Pennsylvania
Desloratadine Interacts with Muscarinic Acetylcholine Receptors with High Affinity and Antagonizes the Cyclic AMP Response at the M2 Subtype
Fexofenadine is highly selective for the H1 receptor, with an excellent therapeutic index. In contrast, desloratadine (a metabolite of loratadine) shows high affinity for muscarinic receptors as well as the H1 receptors, this study found.
While second-generation antihistamines do not cross the blood-brain barrier well, the possibilities for detrimental interactions with heterologous peripheral receptors still exist for both parent compounds and metabolites. The muscarinic receptor family presents the most likely secondary target for antihistamines because it shares the highest degree of sequence homology with the H1 receptor. Therefore, this study investigated the potencies with which desloratadine, loratadine, and fexofenadine interact with muscarinic receptors.
The study involved binding-selectivity experiments in which increasing concentrations of the three drugs were introduced to determine how they competed with the radioligand for the H1 and muscarinic receptors. The functional effects of the drugs were also evaluated by determining their ability to affect cyclic adenosine monophosphate (AMP) accumulation via the M2 muscarinic-receptor subtype.
Potent receptor antagonist
The study found that desloratadine was a potent antagonist of muscarinic acetylcholine receptors, especially the M2 subtype, and had significantly higher affinity for muscarinic receptors than its parent compound, loratadine. In contrast, fexofenadine showed no relevant affinity for muscarinic receptors, reported John Ellis, PhD.
Desloratadine and loratadine both markedly antagonized charbachol-induced inhibition of forskolin-stimulated cyclic AMP formation, while no antagonistic effect could be shown for fexofenadine, even at supraphysiologic doses.
Enhanced selectivity for the H1 receptor is not inevitable in the metabolites of second-generation antihistamines. These data suggest that, relative to muscarinic receptors, fexofenadine is highly selective (600-fold) for the H1 receptor while desloratadine is much less so. These findings suggest that careful pharmacologic characterization of all new antihistamines is advisable to determine whether they represent an improvement over current therapy, Dr. Ellis said.
Key Points In Focus:
- Enhanced selectivity toward the H1
receptor is not inevitable in the
metabolites of second-generation
antihistamines and can influence
the side-effect profile.
- Fexofenadine is highly selective for
the H1 receptor relative to muscarinic receptors.
- Desloratadine
 a metabolite of loratadinehas higher affinity for
muscarinic receptors than does
loratadine.
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