title: Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases.
abstract: Olopatadine (AL-4943A; KW-4679) [(Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2-acetic acid hydrochloride] is an antiallergic/antihistaminic drug under development for topical ocular use. The effects of the compound on release of proinflammatory mediators (histamine, tryptase and prostaglandin D2) from monodispersed human conjunctival mast cells were assessed. Histamine receptor subtype binding affinities and functional potencies were determined with ligand binding and phosphoinositide turnover assays, respectively. Olopatadine inhibited the release of histamine, tryptase and prostaglandin D2, in a concentration-dependent manner (IC50 = 559 microM). Evaluation of the interaction of olopatadine with histamine receptors revealed a relatively high affinity for the H1 receptor (Ki = 31.6 nM, pKi = 7.5 +/- 0.1, n = 7) but lower affinities for H2 receptors (Ki = 100 microM, pKi = 4.0 +/- 0.19, n = 7) and H3 receptors (Ki = 79.4 microM, pKi = 4.1 +/- 0.16, n = 7). The H1 selectivity of olopatadine was superior to that of other ocularly used antihistamines studied, such as ketotifen, levocabastine, antazoline and pheniramine. The profiling of olopatadine in 42 nonhistamine receptor binding assays revealed that olopatadine interacts with only two nonhistamine receptor/uptake sites to any significant degree (pIC50 < or = 5-6). Olopatadine inhibited histamine-induced phosphoinositide turnover in human conjunctival epithelial cells (IC50 = 10 nM, pIC50 = 8.0, n = 4) and in other human ocular cells (IC50 = 15.8-31.6 nM, pIC50 = 7.5-7.8) and exhibited apparent noncompetitive antagonist properties in these cells, with an estimated dissociation constant (Kb) of 19.9 nM (pKb = 7.7, n = 6). This combination of mast cell mediator release inhibition and selective H1 receptor antagonism suggests that olopatadine may be particularly useful in the treatment of ocular allergic diseases. Indeed, olopatadine has recently shown clinical efficacy in an allergic conjunctivitis model in human subjects.
authors.affiliation: 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: S T
authors.initials: ST
authors.lastname: Miller
authors.forename: D A
authors.initials: DA
authors.lastname: Gamache
authors.forename: J M
authors.initials: JM
authors.lastname: Yanni
mesh_terms: D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D053818:Chymases; D003228:Conjunctiva / Q000166:cytology / Q000187:drug effects; D003990:Dibenzoxepins / Q000494:pharmacology*; D005128:Eye Diseases / Q000188:drug therapy*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007665:Ketotifen / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects; D000069605:Olopatadine Hydrochloride; D010716:Phosphatidylinositols / Q000378:metabolism; D015230:Prostaglandin D2 / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D053802:Tryptases
chemical_list: D018926:Anti-Allergic Agents; D003990:Dibenzoxepins; D006634:Histamine H1 Antagonists; D010716:Phosphatidylinositols; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D000069605:Olopatadine Hydrochloride; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases; D015230:Prostaglandin D2; D007665:Ketotifen