title: 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 (Ki = 41.1 +/- 6.0 nM) for H1-receptors and a significantly lower affinity for H2- (Ki = 43,437 +/- 6,257 nM) and H3-receptors (Ki = 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.
authors.affiliation: Molecular Pharmacology Unit, Alcon Laboratories, Inc., Fort Worth, Texas, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Sharif
authors.forename: S X
authors.initials: SX
authors.lastname: Xu
authors.forename: J M
authors.initials: JM
authors.lastname: Yanni
mesh_terms: D018926:Anti-Allergic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D003228:Conjunctiva / Q000378:metabolism; D003233:Conjunctivitis, Allergic / Q000188:drug therapy*; D003315:Cornea / Q000378:metabolism; D003990:Dibenzoxepins / Q000378:metabolism* / Q000627:therapeutic use; D004848:Epithelium / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D000069605:Olopatadine Hydrochloride; D010716:Phosphatidylinositols / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism*; D014129:Trabecular Meshwork / Q000378:metabolism
chemical_list: D018926:Anti-Allergic Agents; D003990:Dibenzoxepins; D006634:Histamine H1 Antagonists; D008024:Ligands; D010716:Phosphatidylinositols; D011968:Receptors, Histamine; D000069605:Olopatadine Hydrochloride; D006632:Histamine