EMEDASTINE - A POTENT, HIGH-AFFINITY HISTAMINE-H-1 RECEPTOR-SELECTIVE ANTAGONIST FOR OCULAR USE - RECEPTOR-BINDING AND 2ND-MESSENGER STUDIES

The antihistaminic agent, emedastine, was tested for its ability to compete for [H-3]pyrilamine, [H-3]tiotidine and [H-3]N-methyl histamine binding to rodent brain H-1, H-2 and H-3 histamine receptors, respectively. Emedastine exhibited the highest affinity for H-1-receptors (dissociation constant, K-i = 1.3 +/- 0.1 nM), and was considerably weaker at H-2- (K-i = 49,067 +/- 11,113 nM) and H-3-receptors (K-i = 12,430 +/- 1,282 nM). These data yielded ratios of 37744, 9562 and 4 for H-2:H-1, H-3:H-1 and H-2:H-3 receptor affinities, respectively, thus making emedastine a very selective H-1-receptor antagonist. The H-1-selectivity of emedastine was considerably superior to that of pyrilamine (H-2:H-1, H-3:H-1 and H-2:H-3 ratios of 11887, 12709 and 1, respectively). Similarly, the respective receptor affinity ratios for ketotifen (858, 1752, 0.5), levocabastine (420, 82, 5), pheniramine (430, 312, 1), chlorpheniramine (5700, 2216, 3) and antazoline (1163, 1110, 1) showed these antihistamines to be also markedly less H-1-selective than emedastine. The potency of emedastine (IC50 = 1.44 +/- 0.3 nM) for antagonizing histamine-induced phosphoinositide turnover in human trabecular meshwork cells compared well with its binding affinity at the H-1-receptor. These data indicate emedastine to be a high affinity and high potency histamine antagonist with the highest selectivity for the H-1-histamine receptor.