MECHANISMS OF ADRENERGIC AGONIST-INDUCED ALLERGY BIOACTIVATION AND ANTIGEN FORMATION

Reduction of elevated intraocular pressure with alpha(2) agonists has proved to be an exciting new therapeutic approach for the treatment of glaucoma. We have studied the chemical reactivities of several alpha( 2) agonists and known allergens to elucidate the origin of the observe d ocular allergic response to the alpha(2) agonist apraclonidine. The oxidation potentials of clonidine, apraclonidine, brimonidine, and two known allergens, amodiaquine, and epinephrine, were measured vs. a st andard calomel electrode. Agents that were oxidatively labile were tre ated with both chemical and enzymatic oxidants. Clonidine and brimonid ine proved to be oxidatively stable in sharp contrast to apraclonidine which had an oxidation potential similar to that observed with epinep hrine and amodiaquine, two known allergy-inducing agents. In addition, two glutathione-apraclonidine conjugates formed by the in-situ reacti on of glutathione with an enzymatically oxidized apraclonidine interme diate were isolated and their structures determined using spectroscopi c methods, The structures were shown to be analogous to those obtained with amodiaquine and epinephrine. Apraclonidine, like amodiaquine and epinephrine, possesses a hydroquinone-like subunit and can be readily oxidized and conjugated with thiols modeling well known hapten-formin g reactions. Brimonidine, like clonidine, lacks the hydroquinone subun it and does not undergo the thiol conjugation reactions. (C) 1997 Acad emic Press Limited.