Olopatadine (AL-4943A): Ligand Binding and Functional Studies on a Novel,Long Acting H1-Selective Histamine Antagonist and Anti-Allergic Agent for Use in Allergic Conjunctivitis

ABSTRACT

AL-4943A (Olopatadine) is a new antihistaminic and anti-allergic drug. It was tested for its ability to compete for [³H]pyrilamine, [³H]tiotidine and [³H]N-methyl histamine binding to H₁, H₂ and H₃ histamine receptors, respectively. AL-4943A exhibited the highest affinity (K_i = 41.1 ± 6.0 nM) for H₁-receptors and a significantly lower affinity for H₂- (K_i = 43,437 ± 6,257 nM) and H₃-receptors (K_i = 171,666 ± 6,774 nM), respectively. These data showed AL-4943A to be an H₁-selective compound, being 1,059- and 4,177-times more selective for H₁- than H₂-and H₃-receptors. AL-4943A was more H₁-selective than levocabastine, ketotifen, antazoline and pheniramine and, also, exhibited a low affinity for 38 nonhistamine receptor binding sites. AL-4943A antagonized histamine-induced phosphoinositide (PI) turnover in cultured human conjunctival epithelial cells (IC₅₀ = 9.5 ± 1.5 nM, n = 3), human corneal fibroblasts (IC₅₀ = 19 nM) and transformed human trabecular meshwork cells (IC₅₀ = 39.9 nM). These data have shown AL-4943A to be a high affinity, high potency H₁-selective histamine antagonist. This information, coupled with a long duration of action in an in vivo model of allergic conjunctivitis, suggests that AL-4943A may be a useful drug to treat various ocular allergic diseases, including allergic conjunctivitis.