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

The antihistaminic agent, emedastine, was tested for its ability to co mpete 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, respecti vely. Emedastine exhibited the highest affinity for H-1-receptors (dis sociation 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 makin g emedastine a very selective H-1-receptor antagonist. The H-1-selecti vity 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 (85 8, 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 emed astine. The potency of emedastine (IC50 = 1.44 +/- 0.3 nM) for antagon izing histamine-induced phosphoinositide turnover in human trabecular meshwork cells compared well with its binding affinity at the H-1-rece ptor. These data indicate emedastine to be a high affinity and high po tency histamine antagonist with the highest selectivity for the H-1-hi stamine receptor.