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

J Ocul Pharmacol Ther. Winter 1996;12(4):401-7. doi: 10.1089/jop.1996.12.401.

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.

MeSH terms

  • Anti-Allergic Agents / metabolism*
  • Anti-Allergic Agents / therapeutic use
  • Binding, Competitive
  • Cell Line
  • Cells, Cultured
  • Conjunctiva / metabolism
  • Conjunctivitis, Allergic / drug therapy*
  • Cornea / metabolism
  • Dibenzoxepins / metabolism*
  • Dibenzoxepins / therapeutic use
  • Epithelium / metabolism
  • Fibroblasts / metabolism
  • Histamine / pharmacology
  • Histamine H1 Antagonists / metabolism*
  • Histamine H1 Antagonists / therapeutic use
  • Humans
  • Hydrolysis
  • Ligands
  • Olopatadine Hydrochloride
  • Phosphatidylinositols / metabolism
  • Receptors, Histamine / metabolism*
  • Trabecular Meshwork / metabolism

Substances

  • Anti-Allergic Agents
  • Dibenzoxepins
  • Histamine H1 Antagonists
  • Ligands
  • Phosphatidylinositols
  • Receptors, Histamine
  • Olopatadine Hydrochloride
  • Histamine