OLOPATADINE (AL-4943A) - LIGAND-BINDING AND FUNCTIONAL-STUDIES ON A NOVEL, LONG-ACTING H-1-SELECTIVE HISTAMINE ANTAGONIST AND ANTIALLERGIC AGENT FOR USE IN ALLERGIC CONJUNCTIVITIS

AL-4943A (Olopatadine) is a new antihistaminic and anti-allergic drug. It was tested for its ability to compete for [H-3]pyrilamine, [H-3]ti otidine and [H-3]N-methyl histamine binding to H-1, H-2 and H-3 histam ine receptors, respectively. AL-4943A exhibited the highest affinity ( K-i = 41.1 +/- 6.0 nM) for H-1-receptors and a significantly lower aff inity for H-2- (K-i = 43,437 +/- 6,257 nM) and H-3-receptors (K-i = 17 1,666 +/- 6,774 nM), respectively. These data showed AL-4943A to be an H-1-selective compound, being 1,059- and 4,177-times more selective f or H-1- than H-2- and H-3-receptors. AL-4943A was more H-1-selective t han levocabastine, ketotifen, antazoline and pheniramine and, also, ex hibited 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-4 943A to be a high affinity, high potency H-1-selective histamine antag onist. This information, coupled with a long duration of action in an in vivo model of allergic conjunctivitis, suggests that AL-4943A may b e a useful drug to treat various ocular allergic diseases, including a llergic conjunctivitis.