HISTAMINE RECEPTOR-SUBTYPE AFFINITIES, SELECTIVITIES, AND POTENCIES OF EMEDASTINE, A NOVEL H-1-SELECTIVE ANTAGONIST, AND OTHER OCULARLY EMPLOYED ANTIHISTAMINES

Emedastine, a novel ocular antihistamine, exhibited nanomolar affinity (K-i = 1.26 nM; pK(i) = 8.9) for the histamine H-1-receptor and had a markedly lower affinity for histamine H-2-(K-i = 39.8 mu M; pK(i) = 4 .4) and H-3-(K-i = 12.6 mu M; pK(i) = 4.9) receptor subtypes. Emedasti ne was the most H-1-selective antagonist tested, being 31,200 and 10,0 80 times more active at the H-1-receptor than at H-2- and H-3-receptor s, respectively. In contrast, while other ocularly employed antihistam ines like pyrilamine, ketotifen, levocabastine, antazoline, and phenir amine had relatively high affinities for the H-1-receptor, they exhibi ted significantly lower H-1-selectivities than emedastine. In general, the H-1-receptor affinities of the compounds compared well with their potencies for antagonizing histamine-induced phosphoinositide (Pi) tu rnover. Emedastine exhibited antagonist potencies (IC50 values) of 1.8 , 1.58, and 0.5 nM in human conjunctival epithelial cells, transformed human trabecular meshwork cells, and human corneal fibroblasts, respe ctively. In conclusion, emedastine is a high affinity and high potency histamine receptor antagonist with a superior H-1-selectivity than ot her antihistamines tested. Emedastine may therefore be a useful antihi stamine for treating symptoms of ocular allergic diseases. (C) 1994 Wi ley-Liss, Inc.